Quinoxaline derivatives useful in therapy

ABSTRACT

Compounds of formula (I), wherein A represents N or CH; R 1  and R 2  independently represent C 1-4  alkyl, halo or CF 3  ; R 3  represents C 1-4  alkyl (optionally substituted), C 3-7  cycloalkyl, CF 3  or aryl; R 4  represents H, C 3-7  cycloalkyl or C 1-6  alkyl (optionally substituted); and their pharmaceutically acceptable derivatives; are useful in the treatment of, inter alia, neurodogenerative disorders. ##STR1##

This application is a 371 of PCT/EP95/03559 which was filed on Sep. 8,1995.

BACKGROUND OF THE INVENTION

This invention relates to quinoxaline derivatives useful in therapy.

L-Glutamic acid is an excitatory amino acid neurotransmitter whosephysiological role in the brain involves interaction with fourreceptors, three of which are named after the selective agonists NMDA(N-methyl-D-aspartate), AMPA(2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate. Thefourth receptor is termed the metabotropic receptor. In addition to abinding site for glutamic acid, the NMDA receptor possesses highaffinity binding sites for dissociative anaesthetics (e.g. ketamine),polyamines (e.g. spermine), glycine and certain metal ions (e.g. Mg²⁺,Zn²⁺). Since the NMDA receptor has an absolute requirement to bindglycine for activation to occur, glycine antagonists can act asfunctional NMDA antagonists.

In the region of a cerebral infarct, for example, anoxia causesabnormally high concentrations of glutamic acid to be released, whichleads to an over-stimulation of NMDA receptors, resulting in thedegeneration and death of neurones. Thus, NMDA receptor antagonists,which have been shown to block the neurotoxic effects of glutamic acidin vitro and in vivo, may be useful in the treatment and/or preventionof pathological conditions in which NMDA receptor activation is thoughtto be important. Examples of such conditions include neurodegenerativedisorders including senile dementia and Alzheimer's disease and thosearising from events such as stroke, transient ischaemic attack,peri-operative ischaemia and traumatic head injury to the brain orspinal cord. They may also have utility in conditions in whichperipheral nerve function has been impaired such as retinal and maculardegeneration.

Furthermore, NMDA antagonists have been shown to possess anti-convulsantand anxiolytic activity and may therefore be used to treat epilepsy andanxiety. They may also be useful in the treatment of pain.

NMDA antagonists may also attenuate the effects of alcohol withdrawalfrom physically dependent animals (K. A. Grant et al. J. Pharm. Exp.Ther. (1992), 260, 1017) and thus NMDA antagonists may be of use in thetreatment of alcohol addiction.

Various derivatives of 1,2,3,4-tetrahydroquinoline-2,4-dione have beendescribed as NMDA (glycine site) antagonists (see EP-A-0459561 andEP-A-0481676), while WO-A-91/13878 and JP-A-3220124 describe1,4-dihydroquinoxalin-2,3-diones as glutamic acid antagonists.WO-A-94/00124 describes 1,4-dihydroquinoxalin-2,3-diones (including6,7-dichloro-5-nitro-1,4-dihydroquinoxalin-2,3-dione) having highaffinity for the glycine binding site with utility for treating strokeand related disorders.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a compound offormula 1, ##STR2## wherein A represents N or CH;

R¹ and R² independently represent C₁₋₄ alkyl, halo or CF₃ ;

R³ represents C₁₋₄ alkyl (optionally substituted by C₃₋₇ cycloalkyl oraryl), C₃₋₋₇ cycloalkyl, CF₃ or aryl;

R⁴ represents H, C₃₋₇ cycloalkyl or C₁₋₆ alkyl optionally substituted byOH, C₁₋₄ alkoxy, aryl (optionally substituted by up to 3 substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halo and CF₃),heterocyclyl (optionally substituted by up to 3 substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, OH, halo, CF₃ andoxo and optionally benzo-fused), C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆alkanoyl, CO₂ H, C₁₋₄ alkoxycarbonyl, NH₂, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, NHSO₂ CF₃, CONR⁵ R⁶, NHCONR⁵ R⁶ or O(CH₂)_(n) NR⁵ R⁶ !;

R⁵ and R⁶ independently represent H or C₁₋₄ alkyl, or taken togetherwith the nitrogen atom to which they are attached they may represent apyrrolidino, piperidino or morpholino group; and

n represents 2, 3 or 4;

or a pharmaceutically acceptable salt thereof (referred to togetherherein as "the compounds of the invention").

Pharmaceutically acceptable salts include salts of acidic or basicgroups which may be present (for example sodium salts of carboxylic acidgroups and hydrochloride salts of amino groups).

Preferably, A represents N.

"Halo" means fluoro, chloro, bromo or iodo. Preferred groups are fluoro,chloro and bromo.

Preferred groups which R¹ and R² independently represent are halo andC₁₋₄ alkyl. For example, they may both represent chlorine, or one mayrepresent chlorine and the other may represent methyl or ethyl.

"Aryl" means an aromatic hydrocarbon such as naphthyl or moreparticularly phenyl.

Preferably, R³ represents C₁₋₄ alkyl, more preferably methyl.

"Heterocyclyl" means an aromatic or non-aromatic heterocyclic groupcontaining one or more heteroatoms each selected from O, S and N. It canbe attached to the C₁ -C₆ alkyl group by a nitrogen or more preferably acarbon atom. Heterocyclyl groups which may be mentioned are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl and thiazolyl. Heterocyclyl groups having afused benzene ring include benzimidazolyl.

Preferably, R⁴ represents C₁₋₆ alkyl substituted by OH or CO₂ H, morepreferably it represents CH₂ CH₂ OH or CH₂ CO₂ H.

Alkyl, alkoxy, alkenyl, alkynyl and alkanoyl groups, where appropriate,can be straight or branched.

Compounds of formula I in which an O or N atom in R⁴ is connected to Avia a single carbon atom may not be sufficiently stable to be used asdrug compounds. Any such unstable compounds do not form part of theinvention.

In some instances the compounds of the invention may exist as tautomersand all such tautomers are included within the scope of the invention,whether separated or not. In addition compounds containing asymmetriccentres can exist as enantiomers and diastereoisomers, and the inventionincludes the separated individual isomers as well as mixtures ofisomers.

In particular, rotation about the bond between A and the1,4-dihydro-2,3-dioxoquinoxaline ring may be restricted, and soatropisomerism may arise. Preferably, when A represents N, R⁴ isdisposed above the plane of the paper and SO₂ R³ is disposed below theplane of the paper in formula I, as shown in formula IA below: ##STR3##The stereochemical assignment of this bond is (R) when R¹ represents Cl,and (S) when R¹ represents methyl, for example.

Optical isomers (including atropisomers) may be separated usingconventional techniques such as fractional crystallization ofdiastereomeric derivatives for example see Example 80(b)!.

DETAILED DESCRIPTION OF THE INVENTION

There is further provided a process for the production of a compound ofthe invention, which comprises removing the protecting groups from acompound of formula II, ##STR4## wherein A and R¹⁻⁴ are as defined aboveand P¹ and p² are protecting groups for hydroxy groups attached toaromatic rings, and where desired or necessary converting the resultingcompound into a pharmaceutically acceptable salt or vice versa.Protecting groups which P¹ and p² may represent include benzyl and C₁₋₆alkyl, in particular methyl. These protecting groups may be removedusing conventional deprotection methods (see `Protective Groups inOrganic Synthesis` by T W Greene and P G M Wuts, John Wiley and SonsInc, 1991). For example, when they represent methyl, they may be removedby acidic hydrolysis using dilute aqueous hydrochloric acid (e.g. 2molar). The reaction is typically carried out by heating the compound offormula II, preferably under reflux, in a mixture of dilute aqueoushydrochloric acid and a suitable organic solvent such as dioxane oracetone for, say, 2 to 48 hours until reaction is complete. The compoundof the invention can then be isolated and purified by conventionalprocedures.

Compounds of formula II, as defined above, form a further aspect of theinvention.

Compounds of formula II in which R⁴ is other than hydrogen may beprepared by reaction of a corresponding compound of formula II in whichR⁴ is H with the appropriate halide of formula R^(4a) X, wherein X isCl, Br or I, and R^(4a) has the same significance as R⁴ as defined aboveexcept that it cannot represent H, in the presence of a base such aspotassium t-butoxide. Typically the base is added to a solution of thecompound of formula II (in which R⁴ represents H) in a suitable organicsolvent such as dimethylformamide. After stirring for a few minutes, thehalide R⁴ X is added and the mixture stirred for a few hours at aboutroom temperature see e.g. Example 7 (a)!. The desired intermediate canthen be isolated and purified by conventional procedures.

In addition, compounds of formula II can be prepared from othercompounds of formula II using conventional methods. For example,compounds in which A is CH, and R⁴ is allyl may be converted tocompounds in which R⁴ is 2-hydroxyethyl by ozonolysis followed byreduction. Compounds of formula II in which A is CH, and R⁴ is allyl mayalso be prepared from corresponding compounds of formula II in which R⁴is H by reaction with diallyl carbonate (e.g. see Example 93).

As an alternative to the above alkylation procedure when A is N, theMitsunobu reaction can be used. This involves the reaction of an alcoholof the formula R^(4a) OH (in which R^(4a) is as defined above) withdiethyl azodicarboxylate, triphenylphosphine and a compound of formulaII in which R⁴ is H. The reaction is typically carried out in a suitableorganic solvent, e.g. tetrahydrofuran, at about room temperature withstirring for, say, 6-12 hours see e.g. Example 49 (a)!.

Compounds of formula II in which R⁴ is a C₁ -C₆ alkyl group substitutedby hydroxy can also be prepared by, or analogously to, the methods ofPreparations 8 to 10, which involve the formation of an alkanoylalkylderivative which is either reduced with e.g. diisobutylaluminium hydrideor reacted with an alkylmagnesium halide.

Compounds of formula II in which R⁴ is hydrogen and A is N can beprepared by sulphonylation of a corresponding quinoxaline of formulaIII, ##STR5## in which R¹, R², p¹ and p² are as defined above, using anappropriate sulphonyl chloride R³ SO₂ Cl or anhydride of formula (R³SO₂)₂ O, in which R³ is as defined above, in a suitable organic solvent,e.g. dichloromethane or tetrahydrofuran, in the presence of an acidacceptor such as pyridine (see e.g. Preparation 5) or triethylamine.With some starting materials, if a large excess of the sulphonylchloride or anhydride is used, then di-sulphonylation or some degree ofdi-sulphonylation may occur. In this situation, one of the R³ SO₂ --substituents can be removed by reaction of the di-sulphonylated productwith aqueous sodium hydroxide (see e.g. Preparation 3). Compounds offormula III can be prepared by conventional techniques such as thoseillustrated in Preparations 1 and 2.

Compounds of formula II in which R⁴ is hydrogen and A is CH may beprepared by reaction of a compound of formula IV, ##STR6## in which R¹,R², p¹ and p² are as defined above, with a thiolate of formula NaSR³, inwhich R³ is as defined above, followed by oxidation using a peracid suchas 3-chloroperbenzoic acid (see for example Preparation 29). Compoundsof formula IV may be prepared by conventional techniques (see forexample Preparation 28).

In the synthesis of the compounds of the invention it may be necessaryor desirable to protect sensitive functional groups and then deprotectthem. Methods for such operations are known to those skilled in the artand are described in `Protective Groups in Organic Synthesis` mentionedabove.

The compounds of the invention are useful because they possesspharmacological activity in animals (including humans). In particular,the compounds are useful in the treatment or prevention ofneurodegenerative disorders (including senile dementia, Alzheimer'sdisease and those arising from events such as stroke, transientischaemic attack, peri-operative ischaemia and traumatic head injury tothe brain or spinal cord; and retinal and macular degeneration),convulsions, pain and anxiety. The treatment of stroke is of particularinterest.

Thus, according to another aspect of the invention, there is provided ananxiolytic, anticonvulsant, analgesic or neuroprotective method oftreatment, which comprises administration of a compound of the inventionto a patient in need of 8 such treatment. The use of the compounds ofthe invention as pharmaceuticals, and the use of the compounds of theinvention in the manufacture of an anxiolytic, anticonvulsant, analgesicor neuroprotective medicament, are also provided.

The biological activity of the compounds of the invention may bedemonstrated in the tests set out below:

(a) Binding affinity for the glycine site of the NMDA receptor

This may be measured by testing a compound's ability to displace aselective glycine site radioligand from rat brain membranes as describedin Brit J Pharm (1991), 104, 74. In a variation of this method,thoroughly washed membrane protein is incubated with ³ H!-L-689,560 for90 minutes using tris-acetate buffer (pH 7.4). Displacement of theradioligand, using a range of test compound concentrations, is used toderive IC₅₀ (50% inhibitory concentration) values.

(b) Binding affinity for the AMPA receptor

This may be measured by testing a compound's ability to displace theradioligand ³ H!-AMPA from rat brain membranes. Membrane homogenate isincubated with radioligand (10 nM) in the presence or absence of testcompounds at various concentrations at 4° C. for 45 min. Free and boundradiolabel is separated by rapid filtration, and radioactivity ismeasured by liquid scintillation counting.

(c) Functional in vitro NMDA antagonism

This is demonstrated by the ability of a compound to inhibit thedepolarizations in rat cortical slices induced by NMDA, similar to themethod described in J Med Chem, (1990), 33, 789 and Brit J Pharm (1985),84, 381. In a variation of the procedure, the response to a standardconcentration of NMDA is measured in the presence of a range of testcompound concentration, and the results obtained are used to derive IC₅₀(50% inhibitory concentration) values.

(d) NMDA antagonism in vivo

This can be demonstrated by the ability of a compound to inhibitNMDA-induced wild running in the mouse according to a variation of themethod described in Brit J Pharm Proceedings Supplement (1992), 107,58P. In this model, groups of mice are treated with test compounds atvarious doses prior to administration of NMDA (60 mg/kg i.v.). Thelatency of onset of wild running is recorded and the presence or absenceof this behaviour used to determine an ED₅₀. Probit analysis is used toestimate a dose at which 50% of mice fail to display wild running by 10minutes post NMDA administration.

(e) Blocking of cortical spreading depression

In vivo activity of a compound may also be demonstrated by measuring itsability to block the propagation of electrically-initiated corticalspreading depression in anaesthetised rats. Thus, male rats areanaesthetised and two glass microelectrodes are inserted into the rightparietal cortex to a depth of 0.5-1 mm for recording brain activity. Inaddition, a bipolar stimulating electrode is placed on the dura in frontof the microelectrodes. The dura is then electrically stimulated at 10minute intervals, and the waves of spreading depression are detected bythe microelectrodes, amplified and displayed using a chart recorder.Test compounds are dissolved in water as their sodium salts, orhydrochloride salts (where possible) and administered by i.v. injectionat various doses to determine the minimum dose which blocks thepropagation of the spreading depression.

The compounds of the invention may be administered to a patient in needof treatment by a variety of conventional routes of administration,including oral and intravenous administration. The compounds havepotential for absorption through the gastrointestinal tract and thusadministration by slow release formulations is also possible.

In general, a therapeutically-effective oral dose is likely to rangefrom 0.1 to 100 mg/kg body weight of the subject to be treated,preferably 1 to 10 mg/kg, and an intravenous dose is likely to rangefrom 0.01-10 mg/kg of body weight of subject treated, preferably 0.1-5mg/kg. Where necessary, the compounds may also be administered byintravenous infusion, at a dose which is likely to range from 0.01-1mg/kg/hr. In practice the physician will determine the actual dosagewhich will be most suitable for an individual patient and it will varywith age, weight and response of the particular patient. The abovedosages are exemplary of the average case but there can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of the invention.

Although the compounds of the invention can be administered alone, theywill generally be administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example, oral administration maybe in the form of tablets containing such excipients as starch orlactose, in capsules either alone or in admixture with excipients, or inthe form of elixirs or suspensions containing flavouring or colouringagents. The compounds may be injected parenterally, for exampleintravenously, intramuscularly or subcutaneously. For parenteraladministration they are best used in the form of a sterile aqueoussolution of an appropriate salt of the compound and the solution maycontain other substances such as salts to make it isotonic with blood.

Thus, there is further provided a pharmaceutical formulation comprisinga compound of the invention, in admixture with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

The compounds of the invention may have the advantage that they are morepotent, more soluble, more selective for example being potentantagonists of the NMDA (glycine site) receptor but with little or noaffinity for the AMPA receptor!, less toxic or possess other moredesirable properties than the compounds of the prior art.

The invention is illustrated by the following Examples. Intermediatecompounds may be prepared as described in the following Preparations.

Melting points were determined using a Buchi apparatus in glasscapillary tubes and are uncorrected. Spectroscopic data were recorded onPerkin-Elmer 983 (Infra Red), Fisons Trio 1000 (Mass Spectrometer,thermospray using ammonium acetate in aqueous methanol as carrier), andBruker AC300 and Varian Unity 300 NMR instruments (both 300 MHz), andwere consistent with the assigned structures. Column chromatography wasaccomplished on Kieselgel 60, (230-400 mesh) from E. Merck, Darmstadt.Kieselgel 60 F₂₅₄ plates from E. Merck were used for thin layerchromatography (TLC), and compounds were visualized with UV light orchloroplatinic acid/potassium iodide solution. In cases where compoundsanalyzed as hydrates, the presence of water was evident in the enhancedpeak due to water in the proton NMR spectra. The purity of compounds wascarefully assessed using analytical TLC and proton NMR (300 MHz), andthe latter technique was used to calculate the amount of solvent insolvated samples. In multistep sequences, the purity and structure ofintermediates were verified spectroscopically by proton NMR. Proton NMRshifts are quoted in parts per million downfield from tetramethylsilane.

Some abbreviations familiar to those skilled in the art have been usedin the Examples and Preparations, e.g. Me (methyl), Et (ethyl), Ac(acetyl), h (hour), m (in relation to silica gel-mesh).

EXAMPLE 1N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)ethanesulphonamide##STR7##

A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)ethanesulphonamide(Preparation 4) (100 mg, 0.273 mmol), 2M hydrochloric acid (2 ml) anddioxane (4 ml) was heated at reflux for 2.5 hours, cooled, andconcentrated under reduced pressure. The solid residue was suspended inwater, filtered off, and washed with water and ether to give the titlecompound (90 mg, 98%) as a white solid, m.p. 297° C. (dec.).

Analysis %:-Found: C, 33.97; H, 2.97; N, 11.68. C₁₀ H₉ Cl₂ N₃ O₄ S.H₂ Orequires C, 33.72; H, 3.11; N, 11.79%.

EXAMPLES 2-6

The following Examples, shown in Table 1 were prepared by the method ofExample 1, using the corresponding 2,3-dimethoxyquinoxaline derivative(Preparations 3, 5 to 7 and 12).

                                      TABLE 1                                     __________________________________________________________________________     ##STR8##                                                                                                     Analysis %                                                      m.p.          Found (Required)                              Example                                                                            R.sup.1,R.sup.2                                                                   R.sup.3                                                                             Yield                                                                            (°C.)                                                                     Formula    C   H  N                                      __________________________________________________________________________    2    Cl  CH.sub.3                                                                            51%                                                                              >330                                                                             C.sub.9 H.sub.7 Cl.sub.2 N.sub.3 O.sub.4 S.H.sub.2                            O          31.33                                                                             2.43                                                                             11.88                                                                  (31.56                                                                            2.65                                                                             12.28)                                 3    Cl  Ph    86%                                                                              >300                                                                             C.sub.14 H.sub.9 Cl.sub.2 N.sub.3 O.sub.4 S                                              43.10                                                                             2.16                                                                             10.75                                                                  (43.54                                                                            2.35                                                                             10.88)                                 4    CH.sub.3                                                                          CH.sub.3                                                                            88%                                                                              >300                                                                             C.sub.11 H.sub.13 N.sub.3 O.sub.4 S.0.15H.sub.2                                          46.21                                                                             4.78                                                                             14.46                                                                  (46.20                                                                            4.69                                                                             14.69)                                 5    CH.sub.3                                                                          CH.sub.2 CH.sub.3                                                                   97%                                                                              >315                                                                             C.sub.12 H.sub.15 N.sub.3 O.sub.4 S                                                      48.20                                                                             4.94                                                                             13.61                                                                  (48.48                                                                            5.09                                                                             14.13)                                 6    CH.sub.3                                                                          CF.sub.3                                                                            84%                                                                              >300                                                                             C.sub.11 H.sub.10 F.sub.3 N.sub.3 O.sub.4 S.H.sub.2                           O          37.45                                                                             3.37                                                                             11.83                                                                  (37.19                                                                            3.40                                                                             11.83)                                 __________________________________________________________________________

EXAMPLE 7N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(methyl)-ethanesulphonamide##STR9##

(a) Potassium tert-butoxide (67.5 mg, 1.1 mmol) was added to a stirredsolution ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)ethanesulphonamide(Preparation 4) (200 mg, 0.55 mmol) in dry dimethylformamide (3 ml)under nitrogen at 20° C. After 5 minutes, methyl iodide (38 μl, 1.1mmol) was added and the mixture was stirred at 20° C. for 2 hours. Themixture was concentrated under reduced pressure, partitioned betweenethyl acetate and water, and the combined organic extracts were washedwith dilute aqueous sodium hydroxide. The solution was dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography (eluting with dichloromethane) to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methyl)ethanesulphonamide(150 mg, 79%).

¹ H NMR (300 MHz, CDCl₃): δ=1.51 (3H, t, J7 Hz), 3.35 (3H,s) 3.37 (2H,q, J7 Hz), 4.14 (3H, s), 4.20 (3H,s), 7.92 (1H,s). m/z (thermospray) 380(MH⁺).

(b) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methyl)-ethanesulphonamide(150 mg, 0.39 mmol), 2M hydrochloric acid (4 ml) and dioxane (8 ml) washeated at reflux for 16 hours, cooled, and concentrated under reducedpressure. The solid residue was suspended in water, filtered off, andwashed with water and ether to give the title compound (140 mg, 99%) asa white solid, m.p. >300° C.

Analysis %:--Found: C, 37.69; H, 3.09; N, 11.84. C₁₁ H₁₁ Cl₂ N₃ O₄ Srequires: C, 37.51; H, 3.15; N, 11.93%.

EXAMPLES 8-48

The following examples, shown in Table 2, were prepared by the method ofExample 7, using the corresponding 2,3-dimethoxyquinoxaline derivative(Preparations 3, 4, 6, 7, 11, 12, 13 and 14) and the appropriate alkylhalide i.e. methyl iodide, ethyl iodide, n-butyl bromide,3-(N,N-dimethylamino)propyl chloride, benzyl chloride, phenethylbromide, 2-propyl bromide, 2-methoxyethyl bromide, allyl bromide,cyclopentyl bromide, 2-(morpholino)ethyl chloride, 4-picolyl chloride,2-hydroxyethyl bromide, n-propyl bromide, 2-picolyl chloride,3-hydroxypropyl bromide, chloroacetone, propargyl bromide and2-(bromomethyl)-6-methoxypyridine (the compound of Preparation 22)!.

                                      TABLE 2                                     __________________________________________________________________________     ##STR10##                                                                                                                 Analysis %                       Ex.                        m.p.              Found (Required)                 No.                                                                              R.sup.1,R.sup.2                                                                     R.sup.3                                                                             R.sup.4     (°C.)                                                                       Formula      C   H  N                         __________________________________________________________________________     8 Cl    CH.sub.3                                                                            CH.sub.3    >330 C.sub.10 H.sub.9 Cl.sub.2 N.sub.3 O.sub.4                                     S.0.5H.sub.2 O                                                                              35.07                                                                            2.62                                                                             11.95                                                                  (34.90                                                                            2.83                                                                             12.21)                     9 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         294-297                                                                            C.sub.11 H.sub.11 Cl.sub.2 N.sub.3                                            O.sub.4 S     37.13                                                                            2.98                                                                             11.40                                                                  (37.51                                                                            3.14                                                                             11.93)                    10 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                       260-261                                                                            C.sub.13 H.sub.15 Cl.sub.2 N.sub.3                                            O.sub.4 S     41.42                                                                            4.09                                                                             10.77                                                                  (41.06                                                                            3.98                                                                             11.05)                    11.sup.(a)                                                                       Cl    CH.sub.3                                                                            CH.sub.2 Ph 282-283                                                                            C.sub.16 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.4 S                                     12 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 Ph                                                                      265-266                                                                            C.sub.17 H.sub.15 Cl.sub.2 N.sub.3                                            O.sub.4 S.0.4-dioxane                                                                       47.91                                                                            3.91                                                                              8.86                                                                  (48.16                                                                            3.93                                                                              9.11)                    13 Cl    CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                        >300 C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.4 S     39.38                                                                            3.53                                                                             11.30                                                                  (39.35                                                                            3.58                                                                             11.47)                    14 Cl    CH.sub.3                                                                            CH.sub.2 CHCH.sub.2                                                                       276-277                                                                            C.sub.12 H.sub.11 Cl.sub.2 N.sub.3                                            O.sub.4 S     39.42                                                                            2.97                                                                             11.43                                                                  (39.57                                                                            3.04                                                                             11.54)                    15 Cl    CH.sub.3                                                                             ##STR11##  295(dec)                                                                           C.sub.14 H.sub.15 Cl.sub.2 N.sub.3                                            O.sub.4 S     42.78 (42.86                                                                     3.84 3.85                                                                        10.34 10.71)              16 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 OCH.sub.3                                                               273-274                                                                            C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.5 S     37.96                                                                            3.11                                                                             10.85                                                                  (37.71                                                                            3.43                                                                             10.99)                    17†                                                                       Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      289-291                                                                            C.sub.11 H.sub.11 Cl.sub.2 N.sub.3                                            O.sub.5 S     35.82                                                                            3.04                                                                             11.37                                                                  (35.88                                                                            3.01                                                                             11.41)                    18 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                              225(dec)                                                                           C.sub.14 H.sub.18 Cl.sub.2 N.sub.4                                            O.sub.4 S.HCl                                                                               37.74                                                                            4.49                                                                             12.32                                                                  (37.72                                                                            4.30                                                                             12.57)                    19 Cl    CH.sub.3                                                                             ##STR12##  271-272 (dec)                                                                      C.sub.15 H.sub.18 Cl.sub.2 N.sub.4                                            O.sub.5 S.HCl                                                                               37.73 (38.02                                                                     4.46 4.04                                                                        11.69 11.83)              20 Cl    CH.sub.3                                                                             ##STR13##  278-279                                                                            C.sub.15 H.sub.12 Cl.sub.2 N.sub.4                                            O.sub.4 S.HCl.H.sub.2 O                                                                     38.47 (38.35                                                                     3.38 3.21                                                                        12.33 11.93)              21 Cl    CH.sub.3                                                                             ##STR14##  285-286 (dec)                                                                      C.sub.15 H.sub.12 Cl.sub.2 N.sub.4                                            O.sub.4 S.HCl                                                                               39.96 (39.88                                                                     2.96 2.90                                                                        12.21 12.40)              22 Cl    CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                         197-199                                                                            C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.4 S.0.5-dioxane                                                                       41.38                                                                            4.27                                                                              9.91                                                                  (40.98                                                                            4.17                                                                             10.24)                    23 Cl    CH.sub.2 CH.sub.3                                                                   CH.sub.2 CHCH.sub.2                                                                       >300 C.sub.13 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.4 S     41.51                                                                            3.52                                                                             11.09                                                                  (41.28                                                                            3.46                                                                             11.11)                    24 Cl    CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.2 OH                                                                      >300 C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.5 S.H.sub.2 O                                                                         36.20                                                                            3.48                                                                             10.63                                                                  (36.01                                                                            3.78                                                                             10.50)                    25 CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         287-289                                                                            C.sub.13 H.sub.17 N.sub.3 O.sub.4                                             S.0.15H.sub.2 O                                                                             49.74                                                                            5.42                                                                             13.15                                                                  (49.72                                                                            5.55                                                                             13.38)                    26 CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                                       308-311                                                                            C.sub.15 H.sub.21 N.sub.3 O.sub.4                                                           53.14                                                                            6.37                                                                             12.35                                                                  (53.08                                                                            6.24                                                                             12.38)                    27 CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.2 CHCH.sub.2                                                                       267-268                                                                            C.sub.14 H.sub.17 N.sub.3 O.sub.4                                             S.0.1H.sub.2 O                                                                              51.75                                                                            5.44                                                                             12.91                                                                  (51.71                                                                            5.33                                                                             12.92)                    28 CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      313-314                                                                            C.sub.13 H.sub.17 N.sub.3 O.sub.5                                             S.0.3H.sub.2 O                                                                              46.88                                                                            5.46                                                                             12.60                                                                  (46.92                                                                            5.33                                                                             12.63)                    29 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.2 OH                                                             248-249                                                                            C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.5 S     37.57                                                                            3.57                                                                             10.79                                                                  (37.71                                                                            3.43                                                                             10.99)                    30 Cl    CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.3                                                                286-287                                                                            C.sub.12 H.sub.13 Cl.sub.2 N.sub.3                                            O.sub.4 S     39.19                                                                            3.60                                                                             11.17                                                                  (39.35                                                                            3.58                                                                             11.47)                    31 Cl    CH.sub.3                                                                            CH.sub.2 CCH                                                                              261-263                                                                            C.sub.12 H.sub.9 Cl.sub.2 N.sub.3 O.sub.4                                     S             39.73                                                                            2.40                                                                             11.50                                                (dec)             (39.79                                                                            2.50                                                                             11.60)                    32 Cl    CH.sub.3                                                                            CH.sub.2 COCH.sub.3                                                                       >300 C.sub.12 H.sub.11 Cl.sub.2 N.sub.3                                            O.sub.5 S     37.92                                                                            2.83                                                                             10.86                                                                  (37.90                                                                            2.92                                                                             11.05)                    33 CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                         245-246                                                                            C.sub.14 H.sub.19 N.sub.3 O.sub.4                                                           51.94                                                                            5.82                                                                             12.99                                                                  (51.68                                                                            5.89                                                                             12.91)                    34 CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                   CH.sub.2 CHCH.sub.2                                                                       206-208                                                                            C.sub.15 H.sub.19 N.sub.3 O.sub.4                                                           53.72                                                                            5.74                                                                             12.47                                                                  (53.40                                                                            5.68                                                                             12.45)                    35 Br    CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         302-304                                                                            C.sub.11 H.sub.11 Br.sub.2 N.sub.3                                            O.sub.4 S     30.04                                                                            2.49                                                                              9.40                                                                  (29.95                                                                            2.51                                                                              9.53)                    36 Br    CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      291-293                                                                            C.sub.11 H.sub.11 Br.sub.2 N.sub.3                                            O.sub.5 S     28.72                                                                            2.52                                                                              8.94                                                                  (28.90                                                                            2.43                                                                              9 19)                    37.sup.(b)                                                                       Cl    CH.sub.3                                                                             ##STR15##  300(dec)                                                                           C.sub.15 H.sub.12 Cl.sub.2 N.sub.4                                            O.sub.5 S0.75H.sub.2 O                                                                      40.56 (40.51                                                                     3.13 3.06                                                                        12.34 12.60)              38 6-Cl,7                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      276-279                                                                            C.sub.13 H.sub.16 ClN.sub.3 O.sub.5                                           S.0.1CH.sub.2 Cl.sub.2                                                                      42.63                                                                            4.04                                                                             11.15                        CH.sub.2 CH.sub.3                         (42.62                                                                            4.42                                                                             11.38)                    39.sup.(c)                                                                       6-Cl,7                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         265-269                                                                            C.sub.13 H.sub.16 ClN.sub.3 O.sub.4 S            CH.sub.2 CH.sub.3                                                          40 7-Cl,6                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      298-300                                                                            C.sub.13 H.sub.16 ClN.sub.3 O.sub.5                                                         42.88                                                                            4.15                                                                             11.21                        CH.sub.2 CH.sub.3                         (43.16                                                                            4.46                                                                             11.61)                    41.sup.(d)                                                                       CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.2 CH.sub.2 CH.sub.3                                                                287-291                                                                            C.sub.14 H.sub.19 N.sub.3 O.sub.4 S           42.sup.(e)                                                                       CH.sub.3                                                                            CH.sub.3                                                                            CH.sub.3    >300 C.sub.12 H.sub.15 N.sub.3 O.sub.4 S           43.sup.(f)                                                                       6-Cl,7                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         300-304                                                                            C.sub.11 H.sub.14 ClN.sub.3 O.sub.4 S            CH.sub.3                                                                   44.sup.(g)                                                                       6-Cl,7                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      >300 C.sub.12 H.sub.14 ClN.sub.3 O.sub.5 S            CH.sub.3                                                                   45.sup.(h)                                                                       7-Cl,6                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         289-290                                                                            C.sub.12 H.sub.14 ClN.sub.3 O.sub.4                                                         43.16                                                                            4.11                                                                             11.74                        CH.sub.3                                  (43.44                                                                            4.25                                                                             12.67)                    46.sup.(i)                                                                       7-Cl,6                                                                              CH.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      311  C.sub.12 H.sub.14 ClN.sub.3 O.sub.5                                                         41.53                                                                            4.17                                                                             11.14                        CH.sub.3                (dec)             (41.44                                                                            4.06                                                                             12.08)                    47.sup.(j)                                                                       CH.sub.3                                                                            CF.sub.3                                                                            CH.sub.2 CH.sub.3                                                                         235-237                                                                            C.sub.13 H.sub.14 F.sub.3 O.sub.4 S           48.sup.(k)                                                                       CH.sub.3                                                                            CF.sub.3                                                                            CH.sub.2 CH.sub.2 OH                                                                      239-241                                                                            C.sub.13 H.sub.14 F.sub.3 N.sub.3 O.sub.5                                     S                                             __________________________________________________________________________     Notes to Table 2                                                              .sup.(a) .sup.1 H NMR (300 MHz, DMSOd.sub.6): 3.39(3H, s), 4.74(1H, d, J      14Hz), 4.82(1H, d, J 14Hz), 7.20(4H, m), 7.30(2H, m), 10.24(1H, br s),        12.13(1H, br s).                                                              .sup.(b) Prepared by the method of Example 7(b) using                         N(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N- (6-methoxypyridin-2-yl)me    hyl!-methane-sulphonamide (Preparation 22). During the hydrolysis of the       dimethoxyquinoxaline, the methoxypyridine is converted to the 2pyridone.      .sup.(c) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 0.95(3H, t, J 8Hz)     1.18(3H, t, J 8Hz), 2.70 2H, q, J 8Hz), 3.20(3H, s), 3.71(2H, m), 7.05(1H     s), 10.75(1H, brs), 12.09(1H, br s). m/z (thermospray) 357                    (MNH.sub.4.sup.+), ν.sub.max. (KBr) 3300, 2950, 1720, 1330 and 1150        cm.sup.-1.                                                                    .sup.(d) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 0.80(3H, t, J 8Hz)     1.30(2H, m), 2.19(3H, s), 2.22(3H, s), 3.19(3H, obscured), 3.49(2H, m),       6.98(1H, s), 9.95(1H, brs), 11.83(1H, br s). m/z (thermospray) 326            (MH.sup.+), 343 (MNH.sub.4.sup.+), ν.sub.max. (KBr) 3380, 3220, 1720,      1680 and 1150 cm.sup.-1.                                                      .sup.(e) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 2.19(3H, s),           2.21(3H, s), 3.16(3H, s), 6.95(1H, s), 10.67(1H, br s), 11.82(1H, br s).      m/z (thermospray 298 (MH.sup.+), 315 (MNH.sub.4.sup.+), ν.sub.max.         (KBr) 3225, 1700, 1325, 1140 and 750 cm.sup.-1.                               .sup.(f) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 1.00(3H, t, J 8Hz)     2.35(3H, s), 3.58(3H, s), 3.72(2H, m), 7.12(1H, s), 10.40(1H, br s),          12.01(1H, br s). m/z (thermospray) 349 (MNH.sub.4.sup.+), ν.sub.max.       (KBr) 3450, 3260, 2950, 1700, 1380, 1330, 1150 and 520 cm.sup.-1.             .sup.(g) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 2.31(3H, s),           3.20(3H, s), 3.34(2H, m), 4.02(2H, m), 7.10(1H, s), 10.80(1H, br s),          12.10(1H, br s). m/z (thermospray) 365 (MNH.sub.4.sup.+).                     .sup.(h) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 1.00(3H, t, J 7Hz)     2.30(3H, s), 3.23(3H, s), 3.65(2H, q, J 7Hz), 7.24(1H, s), 10.40(1H, br       s), 11.93(1H, br s). m/z (thermospray) 349 (MNH.sub.4.sup.+).                 .sup.(i) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 2.30(3H, s),           3.19(3H, obscured), 3.34(2H, m), 3.74(1H, m), 4.05(1H, m), 5.98(1H, br s)     7.23(1H, s), 10.92(1H, br s), 11.91(1H, brs). m/z(thermospray) 348            (MH.sup.+), 365 (MNH.sub.4.sup.+).                                            .sup.(j) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 1.05(3H, t, J 8Hz)     2.18(3H, s), 2.22(3H, s), 3.90(2H, m), 7.10(1H, s), 10.82(1H, br s),          11.94(1H, br s). m/z (thermospray) 383 (MNH.sub.4.sup.+).                     .sup.(k) .sup.1 H NMR (300 MHz, DMSOd.sub.6) δ = 2.18(3H, s),           2.22(3H, s), 3.35(1H, m), 3.50(1H, m), 3.70(1H, m), 4.16(1H, m), 6.10(1H,     br s), 7.05(1H, s), 10.85(1H, br s), 11.95(1H, br s). m/z (thermospray)       382 (MH.sup.+), 399 (MNH.sub.4.sup.+).                                        †Alternatively, the compound of Example 17 may be prepared as          follows:                                                                 

(RS)-N-(f1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(2-hydroxyethyl)methanesulphonamide##STR16##

a) A mixture of potassium carbonate (25.81 g, 0.187 mol), 2-bromoethanol(13.26 ml, 0.187 mol) andN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide(Preparation 3) (55.0 g, 0.156 mol) in acetone (2.5 L), was heated atreflux for 20 h, cooled and the acetone removed under reduced pressure.The residue was partitioned between dichloromethane and 1M sodiumhydroxide. The organic layer was then dried (MgSO₄), concentrated underreduced pressure and the residue purified by recrystallisation threetimes from methanol to give(RS)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide(43.7g, 70%) as a white solid, m.p. 240°-242° C.

Analysis %: Found: C,39.35; H,3.78; N,10.55. C₁₃ H₁₅ N₃ O₅ Cl₂ requires:C,39.41; H,3.82; N,10.61%.

b) A mixture of(RS)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide(11.41 g, 0.029 mol) and 2M hydrochloric (300 ml) acid was heated atreflux for 181/2 h then cooled in an ice-bath. The solid was filteredoff, and washed with water to give the title compound (9.65 g, 91%) as awhite solid, m.p. 272-274° C.

Analysis %: Found: C,35.82; H,3.04; N,11.37. C₁₁ H₁₁ N₃ O₅ Cl₂ Srequires: C,35.88; H,3.01; N,11.41%.

EXAMPLE 49N-(1.4-Dihydro-6.7-dichloro-2.3-dioxoquinoxaline-5-yl)-N-(3-pyridylmethyl)methanesulphonamidehydrochloride ##STR17##

(a) Diethyl azodicarboxylate (90 μl, 0.57 mmol) was added to a stirredsolution ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (200mg, 0.57 mmol - see Preparation 3), 3-(hydroxymethyl)pyridine (55 gl, 50.57 mmol), and triphenylphosphine (149 mg, 0.57 mmol) in drytetrahydrofuran (12 ml) under nitrogen at 23° C. After 8 hours, thesolvent was removed under reduced pressure and the residue was purifiedby flash chromatography (gradient elution with ether/methanol) to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(3-pyridylmethyl)methanesulphonamide(145 mg, 57%) as a white solid, m.p. 217° C. (dec.).

¹ H NMR (300 MHz, CDCl₃): δ=3.18 (3H, s), 4.10 (3H, s), 4.14 (3H, s),4.95 (2H, s), 7.17 (1H, dd, J 4 and 6 Hz), 7.68 (1H, dt, J 2 and 6 Hz),7.90 (1H, s), 8.41 (1 H, d, J 2 Hz), 8.48 (1 H, dd, J 2 and 4 Hz). m/z(thermospray) (443 MH⁺).

(b) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(3-pyridylmethyl)-methanesulphonamide(130 mg, 0.293 mmol), 2M hydrochloric acid (2 ml) and dioxane (4 ml) washeated at reflux for 2.5 hours, cooled, and concentrated under reducedpressure. The residue was suspended in water (1 ml), filtered off, andwashed with water and ether to give the title compound (120 mg, 98%) asa white solid, m.p. 234°-235° C. (dec.).

Analysis %: Found:C, 39.67; H, 3.06; N, 12.20;S, 7.05. C₁₅ H₁₂ Cl₂ N₄ O₄S.HCI requires: C, 39.88; H, 2.90; N, 12.40; S, 7.10%.

EXAMPLES 50-65

The following Examples, shown in Table 3, were prepared by the method ofExample 49, using the corresponding 2,3-dimethoxyquinoxaline derivative(Preparations 3 and 4) and the appropriate alcohol (commerciallyavailable and/or as prepared in Preparations 15-19. The tritylprotecting group in Preparations 15-19 is removed simultaneously in thefinal acid hydrolysis step).

                                      TABLE 3                                     __________________________________________________________________________     ##STR18##                                                                                                                Analysis %                        Ex.                                         Found (Required)                  No. R.sup.1, R.sup.2                                                                  R.sup.3                                                                             R.sup.4      m.p.(°C.)                                                                   Formula     C   H  N                          __________________________________________________________________________    50  Cl  CH.sub.3                                                                             ##STR19##   245(dec)                                                                           C.sub.13 H.sub.11 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl                                                                             35.71 (35.43                                                                      3.10 2.75                                                                        16.00 15.89)               51  Cl  CH.sub.3                                                                             ##STR20##   238-239                                                                            C.sub.14 H.sub.13 Cl.sub.2 N.sub.5                                            O.sub.4 S. HCl.H.sub.2 O                                                                  35.85 (35.57                                                                      3.40 3.41                                                                        14.73 14.81)               52  Cl  CH.sub.3                                                                            (CH.sub.2).sub.2 O(CH.sub.2).sub.2 N(CH.sub.2 CH.sub.3).sub.                  2            269-270                                                                            C.sub.17 H.sub.24 Cl.sub.2 N.sub.5                                            O.sub.5 S.HCl                                                                             40.20 (40.52                                                                      4.95 5.00                                                                        10.86 11.12)               53.sup.(a)                                                                        Cl  CH.sub.3                                                                             ##STR21##   235-236                                                                            C.sub.14 H.sub.13 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl                                 54  Cl  CH.sub.3                                                                             ##STR22##   210(dec)                                                                           C.sub.13 H.sub.11 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl                                                                             35.31 (35.43                                                                      2.81 2.75                                                                        15.70 15.89)               55  Cl  CH.sub.2 CH.sub.3                                                                    ##STR23##   >300 C.sub.15 H.sub.15 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl                                                                             38.99 (38.44                                                                      3.35 3.44                                                                        14.92 14.94)               56  Cl  CH.sub.3                                                                             ##STR24##   261-262                                                                            C.sub.18 H.sub.15 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl                                                                             42.93 (42.83                                                                      2.93 3.20                                                                        14.15 13.88)               57  Cl  CH.sub.3                                                                             ##STR25##   235-236                                                                            C.sub.14 H.sub.11 Cl.sub.2 N.sub.3                                            O.sub.5 S   41.29 (41.60                                                                      2.68 2.74                                                                        10.48 10.40)               58.sup.(b),(c)                                                                    Cl  CH.sub.3                                                                             ##STR26##   >300 C.sub.13 H.sub.11 Cl.sub.2 N.sub.5                                            O.sub.4 S                                     59.sup.(b)                                                                        Cl  CH.sub.3                                                                             ##STR27##   >300 C.sub.12 H.sub.10 Cl.sub.2 N.sub.6                                            O.sub.4 S.0.5H.sub.2 O                                                                    34.42 (34.80                                                                      2.40 2.68                                                                        20.45 20.29)               60.sup.(b)                                                                        Cl  CH.sub.3                                                                             ##STR28##   >300 C.sub.12 H.sub.10 Cl.sub.2 N.sub.6                                            O.sub.4 S.0.5H.sub.2 O. 0.375                                                             36.19 (36.25                                                                      2.86 3.16                                                                        18.90 18.79)               61.sup.(b)                                                                        Cl  CH.sub.3                                                                             ##STR29##   >300 C.sub.13 H.sub.11 Cl.sub.2 N.sub.5                                            O.sub.4 S.0.5H.sub.2 O. 0.33CH.sub.3                                                      37.97 (37.78                                                                      2.80 3.17                                                                        16.13 16.52)               62.sup.(b)                                                                        Cl  CH.sub.3                                                                             ##STR30##   240-243                                                                            C.sub.14 H.sub.13 Cl.sub.2 N.sub.5                                            O.sub.4 S.HCl. 0.8H.sub.2 O                                                               36.04 (35.84                                                                      3.31 3.35                                                                        14.43 14.92)               63  Cl  CH.sub.3                                                                             ##STR31##   285-290 (dec)                                                                      C.sub.14 H.sub.12 Cl.sub.2 N.sub.4                                            O.sub.5 S.0.5H.sub.2 O                                                                    39.38 (39.27                                                                      2.84 3.06                                                                        12.83 13.08)               64  Cl  CH.sub.3                                                                             ##STR32##   285-290 (dec)                                                                      C.sub.15 H.sub.12 Cl.sub.2 N.sub.4                                            O.sub.5 S.HCl                                                                             38.81 (38.52                                                                      2.59 2.80                                                                        11.98 11.98)               65  Cl  CH.sub.3                                                                             ##STR33##   >300 C.sub.14 H.sub.11 Cl.sub.2 N.sub.5                                            O.sub.4 S.0.25 H.sub.2 O.0.4                                                              41.47 (41.09                                                                      2.92 3.25                                                                        15.04 15.36)               __________________________________________________________________________     Notes to Table 3:                                                             .sup.(a)1 H NMR (300 MHz, DMSOd.sub.6, broadened signals due to tautomer      interconversion) 2.10(3H, s), 3.22(3H, br s), 4.80(2H, br s), 7.38(1H, s)     8.65(1H, br s), 12.23(1H, br s), 14.0(1H, br s).                              .sup.(b) As mentioned above for the Mitsunobu reaction, the heterocycles      were trityl protected, as described in Preparations 15-19. The trityl         protecting group was removed concurrently with hydrolysis of the              dimethoxquinoxaline, and the trityl containing side product removed by        trituration with acetone.                                                     .sup.(c)1 H NMR(300 MHz, DMSOd.sub.6) δ = 3.22(3H, s), 4.73(1H, d,      J15Hz), 4.89 (1H, d, J15Hz), 7.23(1H, s), 7.47(2H, s), 10.68(1H, br s),       12.10(1H, br s).                                                         

EXAMPLE 66 (RS),(RS)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(2-hydroxypropyl)methanesulphonamide##STR34##

The title compound was prepared from(RS)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxypropyl)methanesulphonamide(Preparation 9) by the method of Example 1; yield 81% of a white solid(a mixture 10 of diastereoisomers), m.p. 291°-292° C. (from water).

Analysis %: Found: C, 37.77; H, 3.15; N, 10.63. C₁₂ H₁₃ Cl₂ N₃ O₅ Srequires: C, 37.71; H, 3.43; N, 10.99%.

EXAMPLE 67N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(2-hydroxy-2-methylpropyl)methanesulphonamide##STR35##

The title compound was prepared fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxy-2-methylpropyl)methanesulphonamide(Preparation 10) by the method of Example 1; yield 83% of a white solid,m.p. 252°-253° C. (dec.)

Analysis %:--Found: C, 39.32; H, 3.71; N, 10.55. C,₁₃ H₁₅ Cl₂ N₃ O₅ Srequires: C, 39.40; H, 3.81; N, 10.60%.

EXAMPLE 68N-(1,4-Dihydro-6-chloro-7-trifluoromethyl-2.3-dioxoquinoxaline-5-yl)-N-ethylmethanesulphonamide##STR36##

(a) A mixture ofN-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide(Preparation 20, 73 mg, 0.2 mmol) and anhydrous potassium carbonate (33mg, 0.24 mmol) in acetone was stirred under reflux for 20 mins.Iodoethane (32 μl, 0.4 mmol) was added, and the mixture was heated for afurther 2 h. Additional iodoethane (32 μl, 0.4 mmol) was added, andheating was continued for a further 4 h. The mixture was concentratedunder reduced pressure and the residue was partitioned between water andethyl acetate. The organic solution was dried (MgSO₄), concentratedunder reduced pressure, and the residue was purified by flashchromatography (gradient elution with dichloromethane/methanol) to giveN-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide(75 mg, 96%), as a white solid.

¹ H NMR (300MHz, CDCl₃) δ=1.16 (3H,t,J7 Hz), 3.20 (3H,s), 3.86 (2H,m),4.16 (3H,s), 5.50 (2H,br s), 8.06 (1 H,s). m/z (thermospray) 399 (MH⁺).

(b) A mixture ofN-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide(step (a) above, 70 mg, 0.18 mmol), 2M hydrochloric acid (3 ml) anddioxane (6 ml) was heated at reflux for 2 h, cooled and concentratedunder reduced pressure. The residue was suspended in water, filtered andthe solid was washed with water. After being dried, the title compound(33 mg, 48%) was obtained as a white solid, m.p. >300° C.

Analysis:--Found: C,37.61; H,2.73; N,10.80. C₁₂ H₁₁ CIF₃ N₃ O₄ Srequires: C,37.36; H, 2.87; N,10.89%.

EXAMPLE 69N-(1,4-Dihydro-6-chloro-7-trifluoromethyl-2,3-dioxoquinoxaline-5-yl)-N-(2-hydroxyethyl)methanesulphonamide ##STR37##

By the method of Example 68 above, the title compound was prepared,substituting 2-bromoethanol for iodoethane. It was obtained as a whitesolid (40 mg, 44% yield for the two steps), m.p. 292°-294° C.

Analysis %:--Found: C,36.17; H,2.73; N,10.26. C₁₂ H₁₁ CIF₃ N₃ O₅ Srequires: C,35.88; H,2.76; N,10.46%.

EXAMPLE 70(RS)-N-(Carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)methanesulphonamide##STR38##

A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide (Preparation 21, 3.17 g, 7.48 mmol), 2M hydrochloricacid (80 ml) and dioxane (80 ml) was heated at reflux for 18 h, cooledand concentrated under reduced pressure to give a yellow solid (2.85 g,100%), m.p. 271° C. (dec).

Analysis %:--Found: C,33.98; H,2.64; N,10.50. C₁₁ H₉ Cl₂ N₃ O₆ S.1/2H₂ Orequires: C,33.77; H,2.58; N,10.74%.

EXAMPLE 71(RS)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide##STR39##

A solution ofN-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide(Example 70, 2.85 g, 7.46 mmol) in dry methanol (100 ml) saturated withhydrogen chloride gas was heated under reflux for 3 h, cooled andconcentrated under reduced pressure to give a yellow solid (2.838 g,96%) m.p. 301° C. (dec).

Analysis %:--Found: C,36.29; H,2.60; N,10.49. C₁₂ H₁₁ Cl₂ N₃ O₆ Srequires: C,36.38; H,2.80; N,10.61%.

EXAMPLE 72N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(N'-methylcarbamoylmethyl)methanesulphonamide##STR40##

A mixture ofN-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide(from Example 71, 150 mg, 0.38 mmol), ethanol (3 ml) and methylamine(33% solution in ethanol, 3 ml) was heated in a closed vessel at 75° C.for 1 h, then 90° C. for 1.5 h. The mixture was cooled and poured slowlyinto an excess of 2M hydrochloric acid. The white precipitate wasfiltered off and dried to afford the title compound (107 mg, 72%), m.p.289° C.

Analysis %:--Found: C,36.24; H,2.99; N,13.98. C₁₂ H₁₂ Cl₂ N₄ O₅ Srequires: C,36.47; H,3.06; N,14.18%.

The compounds shown in Table 4 below were prepared from the compound ofExample 71 by the method of Example 72, using the appropriate amineinstead of methylamine.

                                      TABLE 4                                     __________________________________________________________________________     ##STR41##                                                                                                Analysis %                                        Ex.                         Found (Required)                                  No.                                                                              R.sup.5                                                                              R.sup.6                                                                           m.p.(°C.)                                                                   Formula     C   H  N                                       __________________________________________________________________________    73 H      H   223(dec)                                                                           C.sub.11 H.sub.10 Cl.sub.2 N.sub.4 O.sub.5 S.1.5H.sub.2                        O          32.28                                                                             3.04                                                                             13.59                                                                  (32.37                                                                            3.21                                                                             13.73)                                  74 CH.sub.3                                                                             CH.sub.3                                                                          >300 C.sub.13 H.sub.14 Cl.sub.2 N.sub.4 O.sub.5 S                                              37.92                                                                             3.26                                                                             13.62                                                                  (38.15                                                                            3.45                                                                             13.69)                                  75 CH.sub.2 CH.sub.3                                                                    H   297  C.sub.13 H.sub.14 Cl.sub.2 N.sub.4 O.sub.5 S                                              38.20                                                                             3.23                                                                             13.45                                                                  (38.15                                                                            3.45                                                                             13.69)                                  76 CH(CH.sub.3).sub.2                                                                   H   278(dec)                                                                           C.sub.14 H.sub.16 Cl.sub.2 N.sub.4 O.sub.5 S.0.75H.sub.                       2 O         38.58                                                                             3.89                                                                             12.81                                                                  (38.49                                                                            4.04                                                                             12.83)                                  77 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                                      300(dec)                                                                           C.sub.15 H.sub.16 Cl.sub.2 N.sub.4 O.sub.5 S.H.sub.2                          O           39.71                                                                             3.93                                                                             12.21                                                                  (39.75                                                                            4.00                                                                             12.36)                                  78 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2                                                     300(dec)                                                                           C.sub.15 H.sub.16 Cl.sub.2 N.sub.4 O.sub.6 S.H.sub.2                                      38.41                                                                             3.69                                                                             11.73                                                                  (38.39                                                                            3.87                                                                             11.94)                                  __________________________________________________________________________

EXAMPLE 79 (RS), (RS)-N-(1-Carboxyethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide##STR42##

A 1:1 mixture of the two isomers ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(1 -methoxycarbonyl-1-ethyl)-methanesulphonamide (Preparation 23, 1.40 g, 32 mmol), 2Mhydrochloric acid (40 ml) and dioxane (40 ml) was heated in an autoclaveat 130° C. for 48 h and 150° C. for 24 h. The mixture was cooled,concentrated to low volume under reduced pressure and the solid filteredoff and washed with ether. The product was dissolved in 1M aqueoussodium hydroxide (40 ml) and precipitated by the addition of 2Mhydrochloric acid (to pH3). The white solid was filtered off and driedin vacuo, to give the title compound (1.13 g, 89%), as a mixture ofdiastereomers, m.p. 282° C. (dec).

Analysis %: Found: C,33.68; H,3.17; N,9.61. C₁₂ H₁₁ Cl₂ N₃ O₆ S.0.5H₂ Orequires: C,34.06; H,3.33; N,9.93%.

EXAMPLE 80 (R)- and(S)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(2-hydroxyethyl)methanesulphonamide

(a)(RS)-N-(Carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)methanesulphonamide##STR43##

(i) A mixture of potassium carbonate (42.37 g, 0.3 mol),methylbromoacetate (48.4 ml, 0.51 mol) andN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(Preparation 3) (90 g, 0.256 mol) in acetone (1 .75 L), was heated atreflux for 81/2 h, cooled and the acetone removed under reducedpressure. The residue was stirred with water (1.5 L) for 1/4h, filteredand the solid washed with water then ether to give(RS)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamide(108 g, 100%).

Analysis %: Found: C,39.51; H,3.52; N,9.89. C₁₄ H₁₅ Cl₂ N₃ O₆ Srequires: C,39.63; H,3.56; N,9.90%.

(ii) A mixture of(RS)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide from (i) above, 2M hydrochloric acid (1 L) anddioxan (1 L) was heated at reflux for 18 h, cooled, and concentratedunder reduced pressure. The solid residue was suspended in water (1.5L), filtered off, and washed with water and ether to give the subtitlecompound (95 g, 92%) as a white powder, m.p. 271 0° C. (dec).

Analysis %: Found: C,33.98; H,2.64; N,10.50. C₁₁ H₉ Cl₂ N₃ O₆ S.1/2H₂ Orequires: C,33.77; H,2.58; N,10.74%.

(b)(R)-N-(Carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamideand (S)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl-methanesulphonamide ##STR44##

Quinine (25.48 g, 0.078 mol) in ethanol (300 ml) was added to arefluxing solution of(RS)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide (from step (a), 30 g, 0.078 mol) in ethanol (2.1 L).After 1/2 h at reflux the suspension was filtered hot and the solidwashed with ethanol to give the subtitle compound of (S) stereochemistryas its quinine salt (23.2 g, 41.3%). α!_(D) ²⁵ =-125.7 (c=0.07, MeOH).

The filtrate was allowed to cool to room temperature with stirring, lefta further 1 h then filtered to give the subtitle compound of (R)stereochemistry as its quinine salt (19.1 g, 34%).

α!_(D) ²⁵ =-98.7° (c=0.15, MeOH).

The quinine salts were individually suspended in water (1.3 L) andtreated with concentrated hydrochloric acid (22 ml) with vigorousstirring to give the two subtitle compounds after filtration.

The subtitle compound of (R) stereochemistry was obtained as a whitesolid (9.8 g, 95%) m.p. >218° C. (dec). α!_(D) ²⁵ =+19.4° (c=0.18,MeOH).

Analysis %: Found: C,33.51; H,2.32; N,10.46. C₁₁ H₉ Cl₂ N₃ O₆ S. 1/2H₂ Orequires: C,33.77; H,2.58; N,10.74%.

The subtitle compound of (S) stereochemistry was obtained as a whitesolid (11.9 g, 95%).

(c)(R)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide##STR45##

A mixture of(R)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide (from step (b), 20.34 g, 0.053 mol) and methanol(266 ml) saturated with hydrogen chloride gas, was stirred for 18 h atroom temperature, evaporated to dryness and the residue suspended inmethanol (300 ml). After stirring for 1/2 h, the solid was filtered offto give the subtitle compound, as a single atropisomer (17.5 g, 83%)m.p. 290° C. (dec).

α!_(D) ²⁵ =-1.7° (c=0.12, MeOH).

¹ H NMR (300 MHz, DMSO-d₆): δ=3.1 (3H,s), 3.75 (3H,s), 4.5 (1H,d), 4.85(1H,d), 7.35 (1H,s), 10.8 (1H,br s), 12.2 (1H,br s). m/z (thermospray)396(MH)⁺.

(d)(R)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide##STR46## Lithium aluminium hydride (39.4 ml, 1 molar in THF, 39.4 mmol)was added to(R)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide (from step (c), 9.75 g, 24.6 mmol) intetrahydrofuran (590 ml), cooled in an ice-bath to between 0°-5° C.After 1/4 hour, further lithium aluminium hydride (2.4 ml, 2.46 mmol)was added, the mixture stirred a further 1/2 h and methanol (20 ml) intetrahydrofuran (60 ml) added.

The mixture was evaporated to dryness under reduced pressure and theresidue partitioned between ethyl acetate and 2M hydrochloric acid. Theorganic extracts were dried over sodium sulphate and concentrated underreduced pressure. The residue was purified by flash chromatography usinggradient elution (CH₂ Cl₂ : MeOH containing 10% AcOH 100:0→95:5) to givethe first title compound, as a single atropisomer, (6.0 g, 66%) m.p.293°-294° C.

α!_(D) ²⁵ =+49.0 (c=0.1, 1M aqueous sodium hydroxide).

Analysis %: Found: C,35.89; H,2.83; N,11.42. C₁₁ H₁₁ Cl₂ N₃ O₅ Srequires: C,35.88; H,3.01; N,11.41.

(e)(S)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(methoxycarbonylmethyl)methanesulphonamide##STR47##

The subtitle compound was prepared from(S)-N-carboxymethyl-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide(step (b)) by the method of step (c); yield 78% of a white solid.

¹ H NMR (300 MHz, DMSO-d₆): δ=3.30 (3H,s), 3.75 (3H,s), 4.32 (1H,d),4.85 (1H,d), 7.35 (1H,s), 10.85 (1H,s), 12.60 (1H,s). m/z (thermospray)396 (MH⁺).

(f)(S)-N-(1.4-Dihydro-6.7-dichloro-2.3-dioxoquinoxalin-5-yl-N-(2-hydroyethyl)methanesulphonamide##STR48##

The second title compound was prepared from(S)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamide(step (e)) by the method of step (d); yield 60% of a white solid, m.p.>300°C.

α!_(D) ²⁵ =-45.0 (c=0.1, 1M aqueous sodium hydroxide).

¹ H NMR (300 MHz, DMSO-d₆): δ=3.21 (5H,m), 3.65 (1H,m), 4.03 (1H,m),6.02 (1H,br s), 7.32(1H,s), 11.00(1H,br s), 12.12(1H,br s). m/z(thermospray) 369(MH+).

EXAMPLE 81 (RS),(RS)-N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(1-methoxycarbonylethyl)methanesulphonamide ##STR49##

N-(1-carboxyethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methanesulphonamide(from Example 79, 1 g, 2.53 mmol) in methanol (100 ml) saturated withhydrogen chloride gas was stirred at room temperature for 24 h, then 8 hat 60° C. The solid was filtered off to give the title compound as amixture of diastereomers (431 mg, 42%).

¹ H NMR (300 MHz, DMSO-d₆): δ=1.70 (3H,d), 3.17 (3H,s), 3.77 (3H,s),4.75 (1H,q), 7.39 (1H,s), 11.46 (1H,s), 12.20 (1H,s). m/z (thermospray)413, 415 (MNH₄ ⁺).

EXAMPLE 82 (RS), (RS)-N-(14-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(1-(N'-methylcarbamoyl)ethyl)methanesulphonamide ##STR50##

N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(1-methoxycarbonylethyl)methanesulphonamide(from Example 81, 110 mg, 0.27 mmol) in 33% methylamine in ethanol (6ml) was heated at 100° C. for 5 h in a sealed vessel, cooled and addedto 2M hydrochloric acid (400 ml). The resulting solid was filtered off,dissolved in 1M sodium hydroxide, precipitated with 2M hydrochloric acidand filtered off to give the title compound, as a mixture ofdiastereomers (63 mg, 57%) m.p. 250° C. (dec). Analysis %: Found:C,37.98; H,3.37; N,13.19. C₁₃ H₁₄ Cl₂ N₄ O₅ S requires: C,37.66; H,3.55;N,13.51.

EXAMPLE 83 N-(14-Dihydro-7-chloro-6-fluoro-2.3-dioxoguinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide##STR51##

(a)N-(7-Chloro-6-fluoro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(Preparation 25) was converted by the method of Example 17(a) intoN-(7-chloro-6-fluoro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide.The product was obtained as a white solid (91% yield), m.p. 209°-210° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.18 (3H,s), 3.32 (1H,m), 3.50 (1H,m), 3.74(2H,m), 4.08 (1H,m), 4.14 (3H,s), 4.20 (3H,s), 7.90 (1H,d,J8 Hz). m/z(thermospray) 380 (MH⁺).

(b)N-(7-Chloro-6-fluoro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)-methanesulphonamidefrom step (a)! was converted by the method of Example 17(b) intoN-(1,4-dihydro-7-chloro-6-fluoro-2,3-dioxoquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide. The product was obtained as a white solid (86%),m.p. 298°-300° C.

Analysis %: Found: C,37.44; H,3.00; N,11.79. C₁₁ H₁₁ CIFN₃ O₅ Srequires: C,37.56; H,3.15; N,11.95%.

EXAMPLE 84N-(1,4-Dihydro-6-chloro-7-fluoro-2,3-dioxoguinoxalin-5yl)-N-(2-hydroxyethyl)methanesulphonamide ##STR52##

(a)N-(6-Chloro-7-fluoro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(Preparation 26) was converted by the method of Example 17(a) intoN-(6-chloro-7-fluoro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)-methanesulphonamide.The product was obtained as a white solid (68% yield).

¹ H NMR (300 MHz, CDCl₃): δ=3.26 (3H,s), 3.50 to 4.10 (4H,m), 4.16(3H,s), 4.20 (3H,s), 7.60 (1H,d,J10 Hz). m/z (thermospray) 380, 382(MH⁺).

(b)N-(6-Chloro-7-fluoro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide from step (a)! was converted by the method ofExample 17(b) intoN-(1,4-dihydro-6-chloro-7-fluoro-2,3-dioxo-quinoxalin-5-yl)-N-(2-hydroxyethyl)methanesulphonamide. The product was obtained as a white solid (75%yield), m.p. 290°-291° C.

Analysis %: Found: C,37.62; H,3.10; N,11.88 C₁₁ H₁₁ CIFN₃ O₅ S requires:C,37.56; H,3.15; N,11.95%.

EXAMPLE 85N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide##STR53##

The title compound was prepared fromN-(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide(Preparation 27, 40 mg, 0.101 mmol) by the method of Example 7(b) andwas obtained as a white solid (18 mg, 48%), m.p. >300° C.

Analysis %: Found: C,31.85; H,3.74; N,13.15. C₁₁ H₁₂ Cl₂ N₄ O₄ S.HCL.2/5H₂ O. 1/10CH₂ Cl₂ requires: C,31.79; H,3.36; N,13.36%.

EXAMPLE 86N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide ##STR54##

The title compound was prepared by the method of Example 85 fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)-methanesulphonamide(from Preparation 27(a), 150 mg, 0.285 mmol) as a white solid (131 mg,92%), m.p. >300° C.

¹ H NMR (300 MHz, d₆ -DMSO): δ=3.25 (3H,s), 3.70-3.82 (2H,m), 3.91-4.07(2H,m), 7.25 (1H,s), 7.80 (4H,s), 11.09 (1H,s), 12.15 (1H,s). m/z(thermospray) 497 (MH⁺).

EXAMPLE 87N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)methanesulphonamide ##STR55##

(a) Triethylamine (13 μl, 8 mg, 0.139 mmol) and thentrifluoromethanesulphonic anhydride (223 μl, 39 mg, 0.139 mmol) wereadded dropwise to a stirred solution ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamide(from Preparation 27, 50 mg, 0.126 mmol) in dichloromethane (1.5 ml) at-78° C. under nitrogen. The mixture was stirred for 30 minutes and wasthen allowed to warm to room temperature. The mixture was washed withwater, saturated sodium bicarbonate solution and brine and then dried(MgSO₄). Concentration under reduced pressure gaveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)methanesulphonamide as a pale yellow solid (50 mg, 75%).

¹ H NMR (300 MHz, CDCl₃): δ=3.20 (3H,s), 3.20-3.30 (1H,m), 3.52-3.62(1H,m), 3.86-3.96 (1H,m), 4.04-4.17 (1H,m), 4.18 (3H,s), 4.23 (3H,s),8.00 (1H,s). m/z (thermospray) 527 (MH⁺).

(b) The title compound was prepared by the method of Example 7(b) fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-(N'-trifluoromethanesulphonyl)aminoethyl)methanesulphonamide from step (a)! as a solid (60%), m.p.203.8°-207.7° C.

Analysis %: Found: C,29.13; H,2.77; N,9.96; C₁₂ H₁₁ N₄ S₂ O₆ Cl₂ F₃. H₂O. 3/10Et₂ O requires: C,29.39; H,2.99; N,10.38.

EXAMPLE 88 N-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl-N-(2-methylaminocarbonyl!aminoethyl) methanesulphonamide ##STR56##

(a) Methylisocyanate (8.2 μl, 8.0 mg, 0.14 mmol) was added to a solutionofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamide(from Preparation 27, 50 mg, 0.127 mmol) in dichloromethane (2 ml) atroom temperature under nitrogen. After 30 minutes the mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate and concentrated under reduced pressure to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-methylaminocarbonyl!aminoethyl) methanesulphonamide as a pale yellowfoam (52 mg, 91%).

¹ H NMR (300 MHz, CDCl₃): δ=2.74 (3H,d,J2 Hz), 3.18 (3H,s), 3.36 (2H,m),3.92 (2H,m), 4.15 (3H,s), 4.17 (3H,s), 4.2 (1H,br s), 5.14 (1H,br s),7.96 (1H,s). m/z (thermospray) 452 (MH⁺).

(b) The title compound was prepared by the method of Example 7(b) fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-methylaminocarbonyl!aminoethyl)methanesulphonamide from step (a)! as apale yellow foam (60%).

Analysis %: Found: C,32.90; H,3.90; N,14.50. C₁₃ H₁₅ N₅ O₅ Cl₂ S.21/2H₂O requires: C,33.27; H,4.30; N,14.92%.

¹ H NMR (300 MHz, d₆ -DMSO) δ=2.43 (3H,s), 3.21 (3H,s), 3.59-3.65(2H,m), 3.75-3.86 (2H,m), 7.40 (1H,s), 10.60 (1H,s), 12.11 (1H,s).

EXAMPLE 89 N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(5-tetrazolylmethyl)methanesulphonamide ##STR57##

(a) Chloroacetonitrile (233 μl, 279 mg, 3,69 mmol) was added to arefluxing mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methane-sulphonamide (fromPreparation 3, 1.00 g, 2.84 mmol) and potassium carbonate (0.47 g, 3.41mmol) in acetone (50 ml) under nitrogen. The mixture was refluxed for 18h and was then allowed to cool, and was partitioned between ethylacetate (500 ml) and water (500 ml). The organic phase was dried (MgSO₄)and concentrated under reduced pressure. The residue was purified byflash chromatography (eluting with 0-100% ethyl acetate in hexane andthen 5% methanol in dichloromethane) to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(cyanomethyl)methanesulphonamide as an off-white solid (600 mg, 54%).

¹ HNMR (300 MHz, DMSO-d₆): δ=3.31 (3H,s), 4.07 (3H,s), 4.08 (3H,s), 4.84(1H,d,J=19 Hz), 5.10 (1H,d,J=19 Hz), 8.11 (1H,s).

(b) A mixture ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(cyanomethyl)methanesulphonamide(100 mg, 0.256 mmol) and tributyltin azide (170 mg, 0.512 mmol)(Synthesis, 1976, 329) in toluene (10 ml) was heated at reflux for 18hours. After cooling the mixture was concentrated under reduced pressureand the residue purified by flash chromatography (gradient elution fromdichloromethane to 90:10:1 dichloromethane: methanol:ammonia) to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(5-tetrazolylmethyl)methanesulphonamide as an off-white solid (78 mg, 70%).

¹ HNMR (300 MHz, CDCl₃): δ=3.30 (3H,s), 4.14 (3H,s), 4.18 (3H,s), 5.12(1H,d,J16 Hz), 5.31 (1H,d,J16 Hz), 7.99 (1H,s). m/z (thermospray) 434(MH⁺).

(c) The title compound was prepared by the method of Example 7(b) fromN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(5-tetrazolylmethyl)-methanesulphonamide,but triturating with water instead of ether, to give a white solid(66%), m.p. >300° C.

Analysis %: Found: C,32.79; H,2.15; N,23.25. C₁₁ H₉ N₇ O₄ Cl₂S.1/10Dioxane requires: C,32.99; H,2.38; N,23.62%.

EXAMPLE 90 (1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)methylmethyl sulphone ##STR58##

A mixture of (6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methyl methylsulphone (80 mg, 0.228 mmol) (Preparation 29), 2M hydrochloric acid (1ml) and dioxane (3 ml) was heated at reflux for 3 h, cooled andconcentrated under reduced pressure. The residue was diluted with waterand the white solid obtained was collected by filtration, washed withwater and ether and dried under reduced pressure at 60° C. to give thetitle compound (58 mg, 79%) as a white solid, m.p. >300° C.

Analysis %:--Found: C,37.35; H,2.35; N,8.44. C₁₀ H₈ N₂ O₄ Cl₂ Srequires: C,37.17; H,2.50; N8.67%.

EXAMPLE 91 (1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)methylethyl sulphone ##STR59##

The title compound was prepared from(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methyl ethyl sulphone(Preparation 30) by the method of Example 90 and was obtained as a whitesolid (65%), m.p. >300° C.

Analysis %: Found: C,39.21; H,2.99; N,8.25; S,9.70. C₁₁ H₁₀ N₂ O₄ Cl₂ Srequires: C,39.18; H,2.99; N,8.31; S,9.51%.

EXAMPLE 92 (1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methylbenzyl sulphone ##STR60##

The title compound was prepared from(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl) methyl benzyl sulphone(Preparation 31) by the method of Example 90 and was obtained as a whitesolid (92%), m.p. >300° C.

Analysis %: Found: C,48.30; H,3.12; N,6.65. C₁₆ H₁₂ N₂ O₄ Cl₂ S 0.2dioxane requires: C,48.40; H,3.29; N,6.72%.

EXAMPLE 931-(1,4-Dihydro-6,7-dichloro-2,3-dioxoquinoxaline-5-yl)-3-butenyl methylsulphone ##STR61##

(a) A solution of (6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methylmethyl sulphone (50 mg, 0.142 mmol) (Preparation 29) and diallylcarbonate (41 μl, 40 mg, 0.285 mmol) in dry tetrahydrofuran (0.8 ml) wasadded via cannula to a mixture of tris(dibenzylideneacetone)dipalladium(0 ml).chloroform adduct (7.4 mg, 0.007 mmol) and1,2-bis(diphenylphosphino)ethane (11.3 mg, 0.028 mmol) in drytetrahydrofuran (0.6 ml) under nitrogen at room temperature. The mixturewas stirred at room temperature for 5 minutes and then at reflux for 2hours. The mixture was allowed to cool, was diluted with dichloromethaneand concentrated under reduced pressure. The residue was purified byflash chromatography (eluting with 3:1 hexane:ethyl acetate) to give1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphoneas a mixture of diastereoisomers (approximately 20:1 by

¹ HNMR) as a white foam (29 mg, 52%).

¹ HNMR (300 MHz, CDCl₃): δ=(major diastereoisomer only) 2.93 (3H,s),3.36 (1H,m), 3.84 (1H,m), 4.16 (3H,s), 4.25 (3H,s), 5.00 (2H,m), 5.45(1H,m), 5.60(1H,m), 7.96 (1H,s). m/z (thermospray) 391 (MH⁺).

(b) A mixture of 1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenylmethyl sulphone (from step (a), 27 mg, 0.069 mmol), 2M hydrochoric acid(0.5 ml) and dioxane (1 ml) was warmed at 90° C. for 15 h, cooled andconcentrated under reduced pressure. The residue was sonicated withether and a few drops of methanol and the resulting white solid wascollected by filtration, washed with ether and dried to afford the titlecompound (17 mg, 68%) as a white powder, m.p. 270.5-272° C.

Analysis %: Found: C,42.98; H,3.35; N,7.45. C₁₃ H₁₂ N₂ Cl₂ O₄ Srequires: C,42.99; H,3.33; N,7.71%.

EXAMPLE 941-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl)-3-hydroxypropylmethyl sulphone ##STR62##

(a) Ozone was bubbled through a solution of1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-butenyl methyl sulphone(50 mg, 0.128 mmol) Example 93(a)! in dry dichloromethane (1.3 ml) at-78° C. until a blue colour developed. The mixture was stirred for 5minutes and was then purged with a stream of oxygen and then nitrogen.Methanol (1.3 ml) was added and the mixture allowed to equilibrate at-78° C. before sodium borohydride (12 mg, 0.319 mmol) was added in twoportions. The mixture was stirred for 5 mins and was then allowed towarm to room temperature. The mixture was poured into 2M hydrochloricacid (20 ml) and extracted with dichloromethane (2×20 ml). The combinedextracts were washed with brine (20 ml), dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by flash chromatography(eluting with 1:1 hexane:ethyl acetate) to give1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-hydroxypropyl methylsulphone (35.6 mg, 70%) as a white foam.

¹ H NMR (300 MHz, CDCl₃): δ=2.96 (3H,s), 3.05 (2H,m), 3.51 (1H,m), 3.87(1H,m), 4.15 (3H,s), 4.22 (3H,s), 5.18 (1H, dd, J 6,8 Hz), 7.98 (1H,s)m/z (thermospray) 395 (MH⁺).

(b) A mixture of 1 -(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-3-hydroxypropyl methyl sulphone(step (a)) (32.4 mg, 0.082 mmol), 2M hydrochloric acid (0.5 ml) anddioxane (1 ml) was heated at reflux for 16 hours, cooled andconcentrated under reduced pressure. The residue was sonicated withether and the resulting solid collected by filtration, washed with etherand dried under reduced pressure at 60° C. to give the title compound(24.7 mg, 82%) as a pale yellow solid, m.p. 267°-269° C.

Analysis %: Found: C,39.12; H,3.21; N,7.81. C₁₂ H₁₂ N₂ Cl₂ O₅ Srequires: C,39.25; H,3.29; N,7.63%.

EXAMPLE 951-(1,4-Dihydro-6,7-dichloro-2,3-dioxoguinoxalin-5-yl-4-hydroxybutylmethyl sulphone ##STR63##

A solution of 9-borabicyclo 3.3.1!nonane in tetrahydrofuran (0.5M, 1.07ml, 0.537 mmol) was added to a stirred solution of1-(6,7-dichloro-2,3-dimethyoxyquinoxalin-5-yl)-3-butenyl methyl sulphone(Example 93 (a)) (200 mg, 0.511 mmol) at room temperature undernitrogen. The mixture was stirred for 20 hours and then trimethylamineN-oxide (119 mg, 1.58 mmol) was added in portions. The mixture wasstirred at room temperature for 2 hours and then at reflux for 30minutes, cooled and concentrated under reduced pressure. The residue waspurified by flash chromatography (eluting with 1:1 hexane:ethyl acetatethen neat ethyl acetate) to give1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-4-hydroxybutyl methylsulphone (120 mg, 57%) as a mixture of diastereoisomers (by ¹ HNMR).

¹ H NMR (300 MHz, CDCl₃): δ=(major diastereoisomer only) 1.29 (1 H,m),1.40 (1H,m), 2.66 (1H,m), 2.89 (3H,s), 3.26 (1H,m), 3.65 (2H,m), 4.15(3H,s), 4.22 (3H,s), 5.42 (1H,dd,J6,8 Hz), 7.98 (1H,s). m/z(thermospray) 409 (MH⁺). (b)The title compound was prepared from1-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-4-hydroxybutyl methylsulphone (step (a), 92 mg, 0.225 mmol) by the method of Example 94 (b)and sonication with a mixture of ether, methanol and aiisopropyl etherto give a pale grey solid (43 mg, 53%), m.p. 306°-307.5° C. (singleunassigned diastereoisomer by ¹ HNMR).

Analysis %: Found: C,41.06; H,3.76; N,7.26; C,₁₃ H₁₄ Cl₂ N₂ O₅ Srequires: C, 40.96; H,3.70; N,7.35%.

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.15 (1H,m), 1.32 (1H,m), 2.20 (1H,m),2.37 (1H,m), 3.30 (5H, obscured, m), 5.32 (1H,dd,J6,8 Hz), 7.38 (1H,s),10.31 (1H,s), 12.12 (1H,s).

EXAMPLE 96

The binding affinity for the glycine site of the NMDA receptor of someof the compounds of the examples were determined in test (a) above, andthose found to have an IC₅₀ of less than 50 nM included the compounds ofthe following examples: 1, 8, 17, 29, 40, 56, 70, 80(b) (first compound)and 80(d).

PREPARATION OF SYNTHETIC INTERMEDIATES PREPARATION 15-Amino-6,7-dichloro-2,3-dimethoxyquinoxaline ##STR64##

(a) A mixture of 6,7-dichloro-1,4-dihydro-5-nitroquinoxalin-2,3-dione(Example 1 of WO-A-94/00124, 84 g, 0.34 mol), thionyl chloride (840 ml)and dimethylformamide (0.5 ml) was heated at reflux for 3 hours, cooledand concentrated under reduced pressure. Ethyl acetate (300 ml) wasadded and removed under reduced pressure, followed by petroleum ether(b.p. 100°-120° C.). The solid residue was recrystallised from petroleumether (b.p. 100°-120° C.) to give2,3,6,7-tetrachloro-5-nitro-quinoxaline (78 g, 73%) as a light yellowsolid.

¹ H-NMR (300 MHz, CDCl₃): δ=8.6 (1H, s).

(b) Tin (II) chloride dihydrate (346.3 g, 1.54 mol) was added to asolution of the product from (a) above (96.2 g, 0.31 mol) in ethylacetate (1.8 l). The mixture was heated under reflux for 4 hours, cooledand poured cautiously into an excess of aqueous saturated sodiumbicarbonate. The mixture was filtered through "Celite", (Trade Mark),washing well with ethyl acetate. The filter cake was macerated with moreethyl acetate and the solid material filtered off. The combined ethylacetate solutions were dried (MgSO₄) and concentrated under reducedpressure to give 5-amino-2,3,6,7-tetrachloroquinoxaline (73.4 g, 84%) asa yellow solid.

¹ H NMR (300 MHz, CDCl₃): δ=5.45 (2H, br, s), 7.47 (1H, s). m/z(thermospray) 385 (MH⁺).

(c) A solution of sodium methoxide (25% solution in methanol, 274 ml,1.28 mol) was added to a suspension of5-amino-2,3,6,7-tetrachloroquinoxaline (72.4 g, 0.256 mol) in drymethanol (1 I) and the resulting mixture was heated at reflux for 30minutes. The mixture was cooled, concentrated under reduced pressure,and the residue partitioned between water and ethyl acetate (total of 8I). The organic solution was dried (MgSO₄) and concentrated underreduced pressure. The crude product was purified by trituration withmethanol, followed by dissolution in dichloromethane (2 I) andfiltration. The filtrate was concentrated under reduced pressure to givethe title compound as a yellow solid (55.0 g, 79%).

¹ H NMR (300 MHz, CDCl₃): δ=4.13 (3H, s), 4.14 (3H, s), 5.07 (2H, br s),7.26 (1H, s). m/z (thermospray) 274 (MH⁺).

PREPARATION 2 5-Amino-2,3-dimethoxy-6,7-dimethyl quinoxaline ##STR65##

(a) 1,4-Dihydro-6,7-dimethylquinoxalin-2,3-dione (10.0 g, 52.6 mmol--see J. Liebigs Ann. Chem., 1982, 754-761) was added in portions over10 minutes to concentrated nitric acid (density, 1.42 gcm⁻³, 100 ml) at0° C. After 5 minutes, the cooling bath was removed and the mixture wasstirred at 20° C. for 7 hours, using cooling when necessary. Thesolution was poured into iced water, and the resulting solid filteredoff and dried in vacuo at 75° C. to give1,4-dihydro-6,7-dimethyl-5-nitroquinoxalin-2,3-dione (7.44 g, 60%) as apale yellow solid, m.p. 280-290° C. (dec.) fromdimethylformamide/water).

¹ H-NMR (300 MHz, DMSO-d₆): δ=2.08 (3H, s), 2.25 (3H, s), 7.06 (1H, s),11.70 (1H, br, s), 12.06 (1H, br, s). ν_(max). (KBr) 3185, 1703, 1533,1400, 1355 cm-⁻¹. m/z (thermospray) 253 (MNH₄ ⁺).

(b) A mixture of 1,4-dihydro-6,7-dimethyl-5-nitroquinoxalin-2,3-dione(from step (a), 7.44 g, 31.6 mmol), thionyl chloride (69.2 ml, 0.949mol) and dimethylformamide (0.25 ml, 3.16 mmol) was heated at reflux for3 hours, cooled, and added gradually to a vigorously stirred mixture ofice and water (1.2 I) over 15 minutes. The resulting precipitate wasfiltered off and dried in vacuo at 80° C. to afford2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline (8.34 g, 97%), as a paleorange solid, m.p. 133°-134° C.

¹ H NMR (300 MHz, DMSO-d₆): δ=2.38 (3H, s), 2.54 (3H, s), 8.12 (1H, s).ν_(max). (KBr) 1537, 1388, 1377, 1269, 1163 cm⁻¹. m/z (thermospray) 289(MNH₄ ⁺).

(c) A mixture of 2,3-dichloro-6,7-dimethyl-5-nitroquinoxaline (from step(b), 8.33 g, 30.6 mmol) and stannous chloride dihydrate (34.54 g, 153mmol) in ethyl acetate (300 ml) was heated at reflux for 11 hours. Afurther portion of stannous chloride dihydrate (13.82 g, 61.2 mmol) wasadded and the mixture was heated for 2 hours, cooled and diluted withethyl acetate (500 ml). The mixture was added to saturated aqueoussodium bicarbonate (200 ml) and filtered, washing the filter cake wellwith ethyl acetate. The organic layer was separated, washed withsaturated aqueous sodium bicarbonate (3×100 ml), dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography (gradient elution with methanol/dichloromethane) toafford 5-amino-2,3-dichloro-6,7-dimethylquinoxaline (6.15 g, 83%), as anorange solid, m.p. 178-180° C.

¹ H-NMR (300 MHz, DMSO-d₆): δ=2.38 (3H, s), 2.54 (3H, s), 8.12 (1H, s).ν_(max). (KBr) 3475, 1613, 1267, 1178 cm⁻¹. m/z (thermospray) 242 (MNH₄⁺).

(d) Sodium methoxide (25% solution in methanol, 13.9 ml, 61 mmol) wasadded over 12 minutes to a stirred solution of5-amino-2,3-dichloro-6,7-dimethylquinoxaline (from step (c), 6.15 g,25.4 mmol) in dry tetrahydrofuran (250 ml) under nitrogen at 0° C. Themixture was stirred at 0° C. for 20 minutes, and at room temperature for72 hours. The mixture was diluted with ethyl acetate (750 ml), washedwith water (2×250 ml) and brine (250 ml), dried (MgSO₄), andconcentrated under reduced pressure. The residue was purified by flashchromatography (gradient elution with hexane/dichloromethane) to givethe title compound as a white solid (4.55 g, 77%), m.p. 166°-167° C.

¹ H NMR (300 MHz, CDCl₃): δ=2.32 (3H, s), 2.35 (3H, s), 4.14 (3H, s),4.15 (3H, s), 5.06 (2H, br, s), 7.06 (1H, s). ν_(max). (KBr) 3540, 2950,1600, 1535, 1395, 1335, 1240 cm⁻¹. m/z (thermospray) 234 (MH⁺).

PREPARATION 3N-(6.7-Dichloro-2,3-dimethoxyquinoxalin-5-Ml)methanesulphonamide##STR66##

(a) A mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (seePreparation 1) (10.0 g, 36.5 mmol), methanesulphonic anhydride (31.8 g,183 mmol) and pyridine (14.8 ml, 183 mmol) in dry dichloromethane (150ml) was stirred at 20° C. for 16 hours. The solvent was removed underreduced pressure and the residue dissolved in a mixture of water (5 ml)and tetrahydrofuran (50 ml). After being stirred for 10 minutes, thesolution was partitioned between ethyl acetate and 2M hydrochloric acid.

The combined organic solutions were washed with saturated aqueous sodiumbicarbonate, dried (MgSO₄), and concentrated under reduced pressure.Purification of the residue by flash chromatography (gradient elutionwith hexane/dichloromethane) gave 6,7-dichloro-5-di(methanesulphonyl)amino-2,3-dimethoxyquinoxaline as an off-white solid (12.3 g, 78%), m.p.240°-244° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.62 (6H, s), 4.16 (3H, s), 4.18 (3H, s),8.02 (1H, s). m/z (thermospray) 430, 432 (MH⁺).

(b) Aqueous sodium hydroxide (1M, 145 ml, 145 mmol) was added to asuspension of6,7-dichloro-5-di(methanesulphonyl)amino-2,3-dimethoxyquinoxaline (fromstep (a), 12.28 g, 28.6 mmol) and the mixture was stirred at roomtemperature for 16 hours. The resulting orange solution was treated with2M hydrochloric acid (to pH3) and the solid which precipitated wasfiltered off, washed with water and ether, and dried in vacuo at 80° C.to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide(8.46 g, 84%) as a white solid, m.p. 225°-227° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.42 (3H, s), 4.15 (3H, s), 4.20 (3H, s),7.15 (1H, br, s), 8.02 (1H, s). m/z (thermospray) 352 (MH⁺).

PREPARATION 4N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)ethanesulphonamide##STR67##

The title compound was prepared by the method of Preparation 3 (a) and(b) using ethanesulphonic anhydride J Am Chem Soc, 76, 1222 (1954)! and5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline, and was obtained as apale yellow solid (47% yield), m.p. 174°-176° C.

¹ H-NMR (300 MHz, CDCl₃): δ=1.38 (3H, t, J 7 Hz), 3.56 (2H, q, J 7 Hz),4.13 (3H, s), 4.20 (3H, s), 6.97 (1H, brs), 7.85 (1H, s). m/z(thermospray) 366 (MH⁺).

In this case step (a) resulted in a mixture of products which weretreated as in step (b) of Preparation 3.

PREPARATION 5N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-benzenesulphonamide##STR68##

A mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline(Preparation 1) (548 mg, 2.0 mmol), benzenesulphonyl chloride (1.28 ml,10 mmol) and pyridine (0.8 ml, 10 mmol) in dry dichloromethane (30 ml)was stirred at reflux for 100 hours. The mixture was poured into ethylacetate/water and a white solid was filtered off, washed with water,ethyl acetate, then ether, and dried at 80° C. in vacuo to give thetitle compound (250 mg, 30%), m.p. 292°-293° C.

¹ H NMR (300 MHz, DMSO-d₆): δ=3.53 (3H, s), 4.02 (3H, s), 7.48 (2H, J 8Hz), 7.63 (3H, m), 8.00 (1H, s), 10.22 (1H, br, s). m/z (thermospray)414 (MH⁺).

PREPARATION 6N-(2,3-Dimethoxy-6,7-dimethylquinoxalin-5-yl)-methanesulphonamide##STR69##

A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (fromPreparation 2) (50 mg, 0.214 mmol), methanesulphonic anhydride (187 mg,1.07 mmol) and pyridine (87 ml, 1.07 mmol) in dry tetrahydrofuran (1 ml)was stirred at 20° C. for 2.7 hours. Water (0.3 ml) was added, and themixture was stirred for 40 minutes. The mixture was partitioned betweenethyl acetate (15 ml) and 2M hydrochloric acid (5 ml). The organicsolution was washed with saturated aqueous sodium bicarbonate (5 ml),dried (MgSO₄), and concentrated under reduced pressure to give the titlecompound (63 mg, 94%) as a white solid, m.p. 219° C.

¹ H NMR (300 MHz, CDCl₃): δ=2.46 (3H, s), 2.55 (3H, s), 2.87 (3H, s),4.16 (6H, s), 7.00 (1H, br, s), 7.57 (1H, s). v_(max). (KBr) 3545, 1480,1160 cm⁻¹. m/z (thermospray) 312 (MH⁺).

Analysis %: Found C, 50.02; H, 5.48; N, 13.35; S, 10.51. C₁₃ H₁₇ N₃ SO₄requires C, 50.15; H, 5.50; N, 13.50; S, 10.30%.

PREPARATION 7N-(2,3-Dimethoxy-6,7-dimethylquinoxalin-5-yl)-ethanesulphonamide##STR70##

A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (fromPreparation 2) (50 mg, 0.214 mmol), ethanesulphonyl chloride (138 mg,1.07 mmol) and pyridine (87 μl, 1.07 mmol) in dry tetrahydrofuran (1 ml)was stirred at 20° C. for 3.5 hours. Additional portions ofethanesulphonyl chloride (138 mg, 1.07 mmol) and pyridine (87 ml, 1.07mmol) were added and the mixture was stirred for a further 4 days. Water(0.6 ml) was added, and the mixture was stirred for 40 minutes. Themixture was partitioned between ethyl acetate (15 ml) and 2Mhydrochloric acid (5 ml). The organic solution was washed with water (5ml), saturated aqueous sodium bicarbonate (5 ml), dried (MgSO₄), andconcentrated under reduced pressure to give the title compound (67 mg,96%) as a straw-coloured solid, m.p. 201°-203° C.

¹ H NMR (300 MHz, CDCl1₃): δ=1.35 (3H, t, J 7 Hz), 2.44 (3H, s), 2.54(3H, s), 3.03 (2H, q, J 7 Hz), 4.15 (3H, s), 4.16 (3H, s), 6.96 (1H, br,s), 7.56 (1H, s). ν_(max). (KBr) 3250, 2940, 1480, 1323, 1239, 1157cm⁻¹. m/z (thermospray) 326 (MH⁺).

Analysis %: Found: C, 51.88; H, 6.02; N, 12.43. C₁₄ H₁₉ N₃ SO₄.0.15ethyl acetate requires: C, 51.79; H, 6.01; N, 12.41%.

PREPARATION 8N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-oxypropyl)methanesulphonamide##STR71##

Potassium t-butoxide (246 mg, 2.2 mmol) was added to a stirred solutionof N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (702mg, 2.0 mmol, see Preparation 3) in dry dimethylformamide (10 ml) undernitrogen at 20° C. Chloroacetone (175 ml, 2.2 mmol) was added, and themixture was stirred for 4 hours. The mixture was concentrated underreduced pressure, and the residue was partitioned between 1M aqueoussodium hydroxide and ethyl acetate. The organic extracts were combined,washed with brine, dried (Na₂ SO₄) and concentrated under reducedpressure to give a white solid which was triturated with ether, filteredand dried to give the title compound (720 mg, 88%), m.p. 247°-2480° C.

¹ H NMR (300 MHz, CDCl₃): δ=2.23 (3H, s), 3.42 (3H, s), 4.17 (3H, s),4.23 (3H, s), 4.45 (1H, d, J 18 Hz), 4.74 (1H, d, J 18 Hz), 7.95 (1H,s). m/z (thermospray) 408 (MH⁺).

PREPARATION 9(RS)-N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxypropyl)methanesulphonamide##STR72##

Diisobutylaluminium hydride (1.0M in dichloromethane, 1.0 ml, 1.0 mmol)was added dropwise to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-oxypropyl)-methanesulphonamide (204mg, 0.5 mmol - Preparation 8) in dry dichloromethane (10 ml) undernitrogen at 20° C. After 4 hours, saturated aqueous ammonium chloride (2ml) was added and the mixture was stirred for 15 minutes before beingfiltered through "Arbocel" (Trade Mark) filter aid. The filter cake waswashed with dichloromethane, and the filtrate was dried (Na₂ SO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography (gradient elution with hexane/ether) to give the titlecompound (182 mg, 89%) as a white solid, m.p. 176°-177° C.

Analysis %:--Found: C, 40.67; H, 4.07; N, 10.06. C₁₄ H₁₇ Cl₂ N₃ O₅ Srequires: C, 40.99; H, 4.18; N, 10.24%.

PREPARATION 10

N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-hydroxy-2-methylpropyl)methanesulphonamide ##STR73##

Methylmagnesium bromide (1.4 ml, 1M in di-n-butylether, 1.4 mmol) wasadded dropwise to a solution ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-oxypropyl)methanesulphonamide(143 mg, 0.35 mmol, see Preparation 8) in dry tetrahydrofuran (10 ml)under nitrogen at 5° C. The mixture was allowed to warm slowly to roomtemperature and stirred for 5 hours. Saturated aqueous ammonium chloride(1 ml) was added and the tetrahydrofuran was removed under reducedpressure. The residue was partitioned between water and ethyl acetate (3portions). The combined extracts were dried (Na₂ SO₄), concentratedunder reduced pressure, and the residue was purified by flashchromatography (gradient elution with hexane/ether) to give the titlecompound (105 mg, 75%) as a white solid, m.p. 160° C.

¹ H NMR (300 MHz, CDCl₃): δ=0.97 (3H, s), 1.30 (3H, s), 3.22 (3H, s),3.56 (1H, s), 3.79 (1H, d, J 15 Hz), 3.96 (1H, d, J 15 Hz), 4.14 (3H,s), 4.19 (3H, s), 7.96 (1H, s). m/z (thermospray) 424 (MH⁺).

PREPARATION 11N-(6,7-Dibromo-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide##STR74##

(a) 1,4-Dihydro-6,7-dibromo-5-nitroquinoxalin-2,3-dione (see Example 33,WO-A-94/00124) was converted into6,7-dibromo-2,3-dichloro-5-nitroquinoxaline by the method of Preparation1 (a). The product was obtained as an off-white solid (72% yield), m.p.126°-128° C. (from hexane). ¹ H NMR (300 MHz, CDCl₃): δ=8.50 (1H, s).

(b) The intermediate from (a) above was converted into5-amino-6,7-dibromo-2,3-dichloroquinoxaline by the method of Preparation1 (b). The product was obtained as a yellow solid (61% yield), m.p.108°-110° C. (after purification by flash chromatography). ¹ H NMR (300MHz, CDCl₃): δ=5.55 (2H, br s), 7.68 (1H, s).

(c) The intermediate from (b) above was converted into5-amino-6,7-dibromo-2,3-dimethoxyquinoxaline by the method ofPreparation 1 (c). The product was obtained as a yellow solid, (59%yield), m.p. 148°-150° C. (after purification by flash chromatography).¹ H NMR (300 MHz, CDCl₃): δ=4.13 (6H, s), 5.20 (2H, br s), 7.51 (1H, s).m/z (thermospray) 364 (MH⁺).

(d) The intermediate from (c) above was converted by the method ofPreparation 3(a) into6,7-dibromo-5-di(methanesulphonyl)amino-2,3-dimethoxyquinoxaline (85%yield), as a pale yellow solid, m.p. 204-206 (after purification byflash chromatography). ¹ H NMR (300 MHz, CDCl₃): δ=3.61 (6H, s), 4.15(3H, s), 4.19 (3H, s), 8.20 (1H, s). m/z (thermospray) 520 (MH⁺).

(e) The intermediate from (d) above was converted intoN-(6,7-dibromo-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide by themethod of Preparation 3(b). The product was obtained as a pale yellowsolid (86% yield), m.p. 186°-187° C. ¹ H NMR (300 MHz, CDCl₃): δ=3.45(3H, s), 4.16 (3H, s), 4.21 (3H, s), 7.08 (1H, br, s), 8.09 (1H, s). m/z(thermospray) 442 (MH⁺).

PREPARATION 12N-(2,3-Dimethoxy-6,7-dimethylquinoxalin-5-yl)-trifluoromethanesulphonamide##STR75##

Trifluoromethanesulphonic anhydride (126 ml, 0.75 mmol) was addeddropwise to a solution of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline(Preparation 2) (170 mg, 0.73 mmol) and triethylamine (112 ml, 0.81mmol) in dry dichloromethane (15 ml) under nitrogen at -50° C. Themixture was stirred at -30° C. for 2 hours, poured into water andextracted with three portions of dichloromethane. The product was thenextracted from the dichloromethane using 1M aqueous sodium hydroxide.The aqueous phase was acidified with excess 2M hydrochloric acid, andthe product extracted into dichloromethane (3 portions). The combinedextracts were dried (MgSO₄) and concentrated under reduced pressure togive a white solid (260 mg, 98%).

¹ H NMR (300 MHz, CDCl₃): δ=2.44 (3H, s), 2.49 (3H, s), 4.14 (3H, s),4.15 (3H, s), 7.13 (1H, br s), 7.61 (1H, s). m/z (thermospray) 366(MH⁺).

PREPARATION 13N-(6-Chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide andN-(7-Chloro-6-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide##STR76## (a) 1,2-Diamino-4-chloro-5-ethylbenzene

A mixture of 5-chloro-4-ethyl-2-nitroaniline (supplied by theSigma-Aldrich Library of Rare Chemicals, 2.62g, 13.1 mmol), tin (II)chloride dihydrate (14.7 g, 65.3 mmol) and ethyl acetate (130 ml) washeated under reflux for 22 h. The mixture was cooled and partitionedbetween 1M aqueous sodium hydroxide (500 ml) and ethyl acetate (500 ml).The aqueous layer was extracted with ethyl acetate (250 ml), and thecombined organic solutions were washed with saturated aqueous sodiumchloride (100ml), dried (MgSO₄) and concentrated under reduced pressureto give a white solid (2.70 g, >100%) which was used directly withoutfurther purification.

¹ H NMR (300MHz, CDCl₃) δ=1.19 (3H,t,J 7 Hz), 2.63 (2H,q,J 7 Hz), 3.30(4H, br s), 6.57 (1H,s), 6.70 (1H,s).

(b) 1,4-Dihydro-6-chloro-7-ethylquinoxalin-2,3-dione

A mixture of 1,2-diamino-4-chloro-5-ethylbenzene (from (a), 2.70 g, ca13 mmol), oxalic acid (1.65 g, 18.3 mmol) and 4M hydrochloric acid (66ml) was heated at reflux for 4.6 h, cooled, and the grey solid collectedby filtration and washed with water. The solid was dried in vacuo at 50°C. to afford the title compound (2.34 g, 80%), m.p. >315° C.

Analysis %: Found, C,53.60; H,3.87; N,12.40. C₁₀ H₉ CIN₂ O₂ requires:C,53.47; H,4.04; N,12.47%.

¹ H NMR (300 MHz, DMSO-d₆) δ=1.17 (3H,t,J 7 Hz), 2.66 (2H,q, J 7 Hz),7.05 (1H,s), 7.14 (1H,s), 11.78 (1H, br s), 11.82 (1H, br s).

(c) 1,4-Dihydro-6-chloro-7-ethyl-5-nitroquinoxalin-2,3-dione and1.4-Dihydro-7-chloro-6-ethyl-5-nitroquinoxalin-2,3-dione

1,4-Dihydro-6-chloro-7-ethylquinoxalin-2,3-dione (from (b), 2.34 g, 10.4mmol) was added in small portions over 10 minutes to vigorously stirredconcentrated nitric acid (20 ml) at room temperature. The mixture wasthen heated at 40° C. for 12 h, cooled, and poured into ice water. Theyellow solid which formed was filtered off, washed with water, and driedto give the title compounds (2.55 g, 91%), as a mixture (1.7:1 ratio).

¹ H NMR (300 MHz, DMSO-d₆) δ=1.09-1.19 (3H,m), 2.56 (1.3H,q,J 7 Hz),2.71 (0.7H,q,J 7 Hz), 7.19 (0.4H,s), 7.29 (0.6H,s), 11.95-12.15 (2H, brm). m/z (thermospray) 287 (MNH₄ ⁺).

(d) 2,3,7-Trichloro-6-ethyl-5-nitroquinoxaline and2,3,6-trichloro-7-ethyl-5-nitroquinoxaline

A mixture of the quinoxalines from (c) above (2.75 g, 11 mmol), thionylchloride (28.6 ml, 0.305 mol) and N,N-dimethylformamide (85 μl, 1.0mmol) was heated under nitrogen at reflux for 24 h. The solution wascooled and cautiously added dropwise to stirred ice-water (600 ml).After 1 h, the beige solid was filtered off, washed with water and driedin vacuo to afford a mixture of the title compounds (2.26 g, 67%).Purification of the mixture by flash chromatography (eluting withhexane:dichloromethane =3:1) permitted isolation of small quantities ofthe two isomers for characterisation purposes.

The first eluted isomer had m.p. 106°-109° C.

Analysis %: Found C,39.21; H,1.99; N,13.71 C₁₀ H₆ Cl₃ N₃ O₂ requiresC,39.18; H,1.97; N,13.71%.

¹ H NMR (300 MHz, CDCl₃) δ=1.41 (3H,t,J 7 Hz), 3.06 (2H,q,J 7Hz), 8.02(1H,s).

m/z (thermospray) 323 (MH⁺).

The second isomer had m.p. 88-92° C.

Analysis %: Found C,39.06; H,1.87; N,13.85%

¹ H NMR (300 MHz, CDCl₃) δ=1.35 (3H,t J 8 Hz), 2.98 (2H,q,J 8 Hz), 8.19(1 H,s).

m/z (thermospray) 323 (MH⁺).

(e) 5-Amino-2,3,7-trichloro-6-ethylquinoxalin and5-amino-2,3,6-trichloro-7-ethylquinoxaline

A mixture of quinoxalines from (d) above (200 mg, 0.652 mmol), tin (II)chloride dihydrate (1.03 g, 4.57 mmol) and ethyl acetate (6.5ml) washeated under reflux for 4 h, cooled and diluted with ethyl acetate. Thesolution was washed with 10% aqueous sodium carbonate (25 ml). Theaqueous layer was extracted with ethyl acetate (2×25 ml), and thecombined organic solutions were washed with 10% aqueous sodium carbonate(2×25 ml), saturated aqueous sodium chloride (25 ml), dried (MgSO₄) andconcentrated under reduced pressure to give the title compounds as anorange solid (174 mg, 91%), ratio 1:1.

¹ H NMR (300 MHz, CDCl₃) δ=1.25 (1.5H,t, J 8 Hz), 1.37 (1.5H,t,J 8 Hz),2.84-2.98 (2H,m), 5.05 (1H,br s), 5.28 (1 H, br s), 7.22 (0.5H,s), 7.43(0.5H,s).

(f) 5-Amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline and5-amino-7-chloro-6-ethyl-2, 3-dimethoxyquinoxaline

A mixture of the trichloroquinoxalines from (e) above (169 mg, 0.611mmol) in anhydrous tetrahydrofuran (6 ml) was treated with a solution ofsodium methoxide (0.84 ml, 25% solution in methanol, 1.47 mmol) at 0° C.with stirring. After 3.5 h, the solution was diluted with ethyl acetate,washed with water (2×10 ml), saturated aqueous sodium chloride (10 ml),dried (MgSO₄) and concentrated under reduced pressure. Purification byflash chromatography (eluting with hexane/ethyl acetate 19:1) gave twofractions.

The first eluted compound,5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline (42mg, 26%), wasobtained as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ=1.32 (3H,t,J8 Hz), 2.87 (2H,q,J 7 Hz), 4.18(6H,s), 4.90 (2H,br s), 7.08 (1H,s).

The second eluted compound,5-amino-7-chloro-6-ethyl-2,3-dimethoxy-quinoxaline (57 mg, 35%), wasobtained as a pale green solid.

¹ H NMR (300 MHz, CDCl₃) δ=1.14 (3H,t,J 7 Hz), 2.84 (2H,q,J 7 Hz), 4.12(3H,s), 4.14 (3H,s), 4.70 (2H,br s), 7.22 (1H,s).

(g) N-(6-Chloro-7-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide

Methanesulphonic anhydride (671 mg, 3.85 mmol) was added to a stirredsolution of 5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline (207 mg,0.77 mmol) and anhydrous pyridine (305 mg, 3.85 mmol) in anhydroustetrahydrofuran (7.7 ml) at room temperature. After 72 h, water (3 ml)was added and the mixture was stirred for a further 60 minutes. Themixture was diluted with ethyl acetate and washed with 2M hydrochloricacid (50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50ml) and saturated aqueous sodium chloride (50 ml). The organic phase wasdried (MgSO₄) and concentrated under reduced pressure to give the titlecompound (206 mg, 77%).

¹ H NMR (300 MHz, CDCl₃) δ=1.37 (3H,t,J 8 Hz), 2.89-3.00 (2H,m), 3.39(3H,s), 4.16 (3H,s), 4.19 (3H,s), 7.01 (1H,s), 7.60 (1H,s). m/z(thermospray) 346 (MH⁺).

(h) N-(7-Chloro-6-ethyl-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide

5-Amino-7-chloro-6-ethyl-2,3-dimethoxyquinoxaline was converted to themethane sulphonamide derivative by the method of step (g) above. Theproduct was obtained in 47% yield.

¹ H NMR (300 MHz, CDCl₃) δ=1.25 (3H,t,J 8 Hz), 3.00 (3H,s), 3.28 (2H,q,J7 Hz), 4.17 (3H,s), 4.27 (3H,s), 6.87 (1H,s), 7.83 (1H,s). m/z(thermospray) 346 (MH⁺).

PREPARATION 14N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamideandN-(7-Chloro-2,3-dimethoxy-6-methylquinoxalin-5-yl)methanesulphonamide##STR77##

The following compounds listed below were obtained in an analogousmanner to the 6-chloro-7-ethyl and 7-chloro-6-ethyl derivatives preparedin Preparation 13.

1,4-Dihydro-6-chloro-7-methylquinoxalin-2,3-dione was obtained from 1,2-diamino-4-chloro-5-methylbenzene (supplied by Maybridge Chemicals) asa dark grey solid, m.p. >330° C.

Analysis %: Found; C,51.58; H,2.98; N,13.27; C₉ H₇ CIN₂ O₂ requiresC,51.32; H,3.35; N,13.30%.

1,4-Dihydro-6-chloro-7-methyl-5-nitroquinoxalin-2,3-dione and 1,4-dihydro-7-chloro-6-methyl-5-nitroquinoxalin-2,3-dione were obtained asa yellow solid (1:2 ratio).

¹ H NMR (300 MHz, CDCl₃) δ=2.23 (2H,s), 2.35 (1H,s), 7.19 (0.3H,s), 7.30(0.7H,s), 11.9-12.25 (2H,br m).

2,3,7-Trichloro-6-methyl-5-nitroquinoxaline and2,3,6-trichloro-7-methyl-5-nitro-quinoxaline were obtained as astraw-coloured powder, and could be separated with difficulty forcharacterisation purposes. Flash chromatography (gradient elution withhexane/dichloromethane) gave first the 6-methyl-7-chloro isomer as awhite solid, m.p. 164°-165° C.

Analysis %: Found, C,36.76; H,1.37; N,14.43, C₉ H₄ Cl₃ N₃ O₂ requires:C,36.96; H,1.38; N,14.37%.

The second eluted isomer (7-methyl-6-chloro) was a straw-coloured solid,m.p. 121°-122° C.

Analysis %: Found, C,39.78; H,2.02; N,13.23; C₉ H₄ Cl₃ N₃ O₂. 0.22hexane requires: C,39.80; H,2.29; N,13.49%.

5-Amino-2,3,7-trichloro-6-methylquinoxaline and5-amino-2,3,6-trichloro-7-methylquinoxaline were obtained as a brownsolid.

¹ H NMR (300 MHz, CDCl₃) δ=2.41 (2H,s), 2.55 (1H,s), 5.03 (1.3H, br s),5.08 (0.7H, br s), 7.23 (0.3H,s), 7.44 (0.7H,s).

5-Amino-7-chloro-2,3-dimethoxy-6-methylquinoxaline and5-amino-6-chloro-2, 3-dimethoxy-7-methylquinoxaline were separated byrepeated column chromatography on silica gel, eluting with hexane/ethylacetate =1:1 followed by dichloromethane.

The first eluted compound, the 6-chloro-7-methyl isomer, was obtained asan off-white solid, m.p. 169°-170° C.

Analysis %: Found, C,53.80; H,5.16; N,16.18; C₁₁ H₁₂ CIN₃ O₂. 0.15hexane requires: C,53.61; H,5.33; N,15.76%.

The second eluted compound, the 7-chloro-6-methyl isomer, was obtainedas an orange solid, m.p. 181°-182° C.

Analysis %: Found, C,52.55; H,4.72; N,16.61 C₁₁ H₁₂ CIN₃ O₂. 0.05 hexanerequires: C,52.61; H,4.96; N,16.29%.

N-(6-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamidewas obtained as a white solid m.p. 198° C.

¹ H NMR (300 MHz,CDCl₃) δ=2.58, (3H,s), 3.38 (3H,s), 4.15 (3H,s), 4.18(3H,s), 7.00 (1H,br s), 7.60 (1H,s).

m/z (thermospray) 332 (MH⁺). v_(max). (KBr) 3230, 2950, 1480 and 1150cm⁻¹.

N-(7-Chloro-2,3-dimethoxy-7-methylquinoxalin-5-yl)methanesulphonamidewas obtained as a white solid m.p. 228°-229° C.

Analysis %: Found, C,43.51; H,3.98; N,12.60 C₁₂ H₁₄ CIN₃ O₄ S requires:C,43.44; H,4.25; N,12.60%.

PREPARATION 15 4-Hydroxymethyl-2-(triphenylmethyl)-1,2.3-triazole##STR78##

(a) Methyl 1 H-1,2,3-triazole-4-carboxylate J Org Chem 41, 1041 (1976)!(1.00 g, 7.09 mmol) was added to a stirred suspension of sodium hydride(234 mg, 80% oil dispersion, 7.80 mmol) in anhydrous tetrahydrofuran(100 ml) under nitrogen at room temperature. After 20 minutes themixture was cooled to 0° C. and trityl chloride (2.17 g, 7.80 mmol) wasadded. The mixture was stirred for 4 hours at 0° C. Water (100 ml) wasadded and the tetrahydrofuran was removed under reduced pressure. Theremaining mixture was extracted with ethyl acetate (100 ml). The organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure to afford a solid which was purified by flash chromatography onsilica gel eluting with 5-30% ethyl acetate in hexane. The first elutedproduct was tentatively identified as methyl 1-(triphenylmethyl)-1,2,3-triazole-4-carboxylate and was obtained as a white solid (600 mg,21%).

¹ H NMR (300 MHz, CDCl₃) δ=3.92 (3H,s), 7.11 (6H,m), 7.32 (9H,m), 8.15(1H,s).

The second eluted product was tentatively identified as methyl2-(triphenylmethyl)-1, 2,3-triazole-4-carboxylate and was obtained as awhite solid (500 mg, 18%).

¹ H NMR (300 MHz, CDCl₃) δ=3.94 (3H,s), 7.11 (6H,m), 7.36 (9H,m), 8.02(1H,s).

(b) A solution of lithium aluminium hydride (1.04 ml, 1M intetrahydrofuran, 1.04 mmol) was added dropwise to a stirred solution ofmethyl 2-(triphenylmethyl)-1, 2,3-triazole-4-carboxylate (from step (a),500 mg, 1.38 mmol) in anhydrous tetrahydrofuran (30 ml) at 0° C. undernitrogen. The mixture was stirred for 1 hour at 0° C. and then water (2ml), 15% aqueous sodium hydroxide (4 ml) and then more water (4 ml) wereadded. The resulting suspension was filtered through Arbocel filter aidand the filtrate was dried (MgSO₄) and concentrated under reducedpressure. The residue was partitioned between dichloromethane (150 ml)and water (150 ml). The dichloromethane layer was washed with water (600ml) and then dried (MgSO₄) and concentrated under reduced pressure toleave the title compound as a white solid (401 mg, 85%).

¹ H NMR (300 MHz, CDCl₃) δ=2.05 (1H,t,J7 Hz), 4.81 (2H,d,J7 Hz), 7.12(6H,m), 7.35 (9H,m), 7.47 (1H,s).

PREPARATION 16 4-Hydroxymethyl-5-methyl-1 -(triphenylmethyl)imidazole##STR79##

(a) Sodium hydride (900 mg, 80% oil dispersion, 30 mmol) was added inportions over 5 minutes to a stirred solution of ethyl4-methyl-imidazole-5-carboxylate (3.85 g, 25 mmol) in drytetrahydrofuran (100 ml) at room temperature under nitrogen. After 10minutes, trityl chloride (8.36 g, 30 mmol) was added in one portion.After 1 h, the mixture was diluted with ethyl acetate (500 ml) andwashed with water (200 ml). The washings were extracted with ethylacetate (2×75 ml) and the combined organic solutions were dried (MgSO₄)and concentrated under reduced pressure. The residue was purified byflash chromatography (gradient elution with hexane/ethyl acetate to giveethyl 5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 10%)as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ=1.38 (3H,t,J 6Hz), 1.83 (3H,s), 4.36 (2H,q,J6 Hz), 7.14 (6H,m), 7.35 (10H,m).

(b) A solution of lithium aluminium hydride (7.65 ml, 1M intetrahydrofuran, 7.65 mmol) was added dropwise to a stirred suspensionof ethyl 5-methyl-1 -(triphenylmethyl) imidazole-4-carboxylate (1.01 g,2.55 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen at 0° C.over 1 minute. After 30 minutes, water (300 μl) was added cautiously,followed by aqueous sodium hydroxide (1M, 300 μl) and water (900 μl).The suspension was filtered using Arbocel filter aid and the filter cakewas washed with tetrahydrofuran (2×30 ml). The filtrate was concentratedunder reduced pressure, and the residue was dissolved in boilingmethanol (50 ml). Dichloromethane (200 ml) and anhydrous magnesiumsulphate were added, and the mixture was filtered through Arbocel filteraid. The filtrate was concentrated under reduced pressure to give awhite solid (325 mg, 36%).

¹ H NMR (300 MHz, CDCl₃) δ=1.47 (3H,s), 4.05 (2H,s), 7.14 (6H,m), 7.35(10H,m).

PREPARATION 17 4-Hydroxymethyl-1 -(trilhenylmethyl)pyrazole ##STR80##

(a) Ethyl 1 H-pyrazole-4-carboxylate (1.50 g, 10.7 mmol) was added inportions to a stirred suspension of sodium hydride (353 mg, 80% oildispersion, 11.8 mmol) in anhydrous tetrahydrofuran (100 ml) undernitrogen at room temperature. After 20 minutes, the mixture was cooledto 0° C. and trityl chloride (3.28 g, 11.8 mmol) was added. The mixturewas stirred at 0° C. for 4 h and allowed to warm to room temperatureovernight. The mixture was then heated at 50° C. for 3 h, cooled, andfurther portions of sodium hydride (321 mg, 10.7 mmol) and tritylchloride (1.0 g, 3.59 mmol) were added. The mixture was heated at 50° C.for 2 h, cooled, treated with water (50 ml) and concentrated underreduced pressure. The product was extracted into ethyl acetate (200 ml),the solution was dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by flash chromatography (gradient elution withhexane/ethyl acetate) to give ethyl 1-(triphenylmethyl)-pyrazole-4-carboxylate (2.273 g, 56%), as a whitesolid.

¹ H NMR (300 MHz, CDCl₃) δ=1.31 (3H,t,J 7 Hz), 4.27 (2H,q, J 7 Hz), 7.13(6H,m), 7.32 (9H,m), 7.94 (1H,s), 8.02 (1H,s).

(b) Lithium aluminium hydride (1M solution in tetrahydrofuran, 4.45 ml,4.45 mmol) was added dropwise to a stirred solution of ethyl1-(triphenylmethyl)-pyrazole-4-carboxylate (2.27 g, 5.93 mmol) inanhydrous tetrahydrofuran (300 ml) under nitrogen at 0° C. After 1 h,the mixture was treated sequentially with water (3 ml), 15% aqueoussodium hydroxide (3 ml) and water (6 ml). The mixture was filteredthrough Arbocel filter aid, the filtrate was dried (MgSO₄) andconcentrated under reduced pressure, to give4-hydroxymethyl-1-(triphenylmethyl) pyrazole (1.746g, 86%), as a whitesolid.

¹ H NMR (300 MHz, CDCl₃) δ=1.43 (1H,brs), 4.35 (2H,s), 7.16 (6H,m), 7.26(9H,m), 7.37 (1H,s), 7.68 (1H,s).

PREPARATION 18 3-Hydroxymethyl-1-(triphenylmethyl)-1,2,4-triazole##STR81##

Triethylamine (1.13 ml, 8.08 mmol) was added to a suspension of3-hydroxymethyl-1 H- 1, 2,4-triazole J Am Chem Soc, 77, 1538 (1955)!,(400 mg, 4.04 mmol) in dry dichloromethane (8 ml) at 0° C. A solution oftrityl chloride (1.24 g, 4.44 mmol) in anhydrous tetrahydrofuran wasadded, and the mixture was stirred at room temperature for 3 h. Themixture was partitioned between water (75 ml) and dichloromethane (75ml). The organic layer was dried (MgSO₄) and concentrated under reducedpressure to give the title compound (1.547 g, >100%) which was usedwithout purification.

¹ H NMR (300 MHz, CDCl₃) δ=4.77 (2H,s), 7.13 (6H,m), 7.32 (9H,m), 7.95(1 H,s).

PREPARATION 19 3-(Hydroxymethyl)-1 -(triphenylmethyl)pyrazole ##STR82##

This compound was prepared from 3-(hydroxymethyl)-1 H-pyrazole, J. Am.Chem. Soc, 71, 3996, (1949)!, trityl chloride and trimethylamine usingthe method of Preparation 18, above. The crude product was purified byflash chromatography (gradient elution with hexane/ethyl acetate) togive a white solid (1.428 g, 60%).

¹ H NMR (300 MHz, CDCl₃) δ=1.14 (1 H,t,J 5 Hz), 4.67 (2H,dd,J 2 and 5Hz), 6.22 (1H,d,J 2 Hz), 7.16 (6H,m), 7.30 (10H,m).

m/z (thermospray) 341 (MH⁺).

PREPARATION 20N-(3-Amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide##STR83## (a) 1,2-Diamino-4-chloro-5-trifluoromethyl benzene

A solution of sodium dithionite (51.0 g, 293 mmol) in water (700 ml) wasadded to a stirred mixture of 5-chloro-4-trifluoromethyl-2-nitroanilineKhim Geterotsikl Soedin, 1136 (1976)! (23.5 g, 97.7 mmol) and potassiumbicarbonate (51.0 g) in methanol (700 ml) at room temperature. After 30minutes, the mixture was concentrated under reduced pressure, and theresidue was partitioned between dichloromethane and water. The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure to give an orange solid (13.3 g, 65%).

¹ H NMR (300 MHz, CDCl₃) δ=3.37 (2H, br s), 3.70 (2H, br s), 6.78(1H,s), 6.98 (1H,s).

(b) 1,4-Dihydro-6-chloro-7-trifluoromethylquinoxalin-2,3-dione

A mixture of 1,2-diamino-4-chloro-5-trifluoromethylbenzene (13.4 g, 63.6mmol) and diethyl oxalate (100 ml) was heated at reflux under nitrogenwith stirring for 5 h. After being cooled, the solid which formed wasfiltered off and washed well with ether to afford a pale orange solid(14.5 g, 86%).

Analysis%: Found, C,40.93; H,1.35; N,10.43: C₉ H₄ ClF₃ N₂ O₂ requires:C,40.85; H,1.52; N,10.59%.

(c) 1,4-Dihydro-6-chloro-7-trifluoromethyl-5-nitroquinoxalin-2,3-dioneand 1,4-dihydro-7-chloro-6-trifluoromethyl-5-nitroquinoxalin-2,3-dione

1,4-Dihydro-6-chloro-7-trifluoromethylquinoxalin-2,3-dione (from step(b), 14.06 g, 53.1 mmol) was added in portions to stirred fuming nitricacid (100 ml) at 0° C. The mixture was allowed to warm to 20° C. over 30minutes after the addition was complete, and the resulting solution waspoured onto iced water and the solid which precipitated was filteredoff, washed with water, and dried to afford a pale orange solid (15.06g, 92%), as a 2:1 mixture of isomers.

¹ H NMR (300 MHz, DMSO-d₆) δ=7.42 (1 H minor,s), 7.62 (1H major,s),12.33 (1H major, 1H minor,br s), 12.51 (1H major, 1H minor,br s).

(d) 2,3,6-Trichloro-7-trifluoromethyl-5-nitroquinoxaline and 2,3,7-trichloro-6-trifluoromethyl-5-nitroquinoxaline

A mixture of the quinoxalindiones from (c) above, (14.7 g, 47.5 mmol)thionyl chloride (140 ml) and dry dimethylformamide (1.4 ml) was heatedat reflux for 30 minutes, cooled and added dropwise to iced water. Thesolid which formed was extracted into ethyl acetate and the solution waswashed with one portion of saturated aqueous sodium bicarbonate, and twoportions of water. The solution was dried (MgSO₄) and concentrated underreduced pressure to give a yellow oil (17.9 g, 100%).

¹ H NMR (300 MHz, CDCl₃) δ=8.33 (1H minor,s), 8.58 (1H major,s).

(e) 6-Chloro-7-trifluoromethyl-2,3-dimethoxy-5-nitroquinoxaline and7-chloro-6-trifluoromethyl-2,3-dimethoxy-5-nitroquinoxaline

Sodium hydride (0.95 g, 80% oil dispersion, 31.7 mmol) was added inportions to a stirred solution of a mixture of the trichloroquinoxalinesfrom (d) above (5.0 g, 14.4 mmol) in anhydrous methanol (125 ml) at roomtemperature. After 18 h, the mixture was concentrated under reducedpressure, diluted with water and the resulting solid was filtered off,washed with water, and dried, to afford a white solid (4.4 g, 90%), as a2:1 mixture of isomers.

¹ H NMR (300 MHz, CDCl₃) δ=4.10 (3H minor,s), 4.15 (3H major,s), 4.20(3H major, 3H minor,s), 8.00 (1H minor,s), 8.25 (1H major,s).

(f) 3-Amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitroquinoxaline and3-amino-7-chloro-6-trifluoromethyl-2-methoxy-5-nitroquinoxaline

A mixture of the dimethoxyquinoxaline isomers from (e) above (0.5 g, 1.5mmol) and saturated methanolic ammonia (7 ml) was heated at 100° C. in aclosed pressure vessel for 4 h. The mixture was cooled, poured intowater and extracted with three portions of ethyl acetate. The combinedextracts were dried (MgSO₄) and concentrated under reduced pressure. Thereaction was repeated on the same scale, and the crude products werecombined and purified by flash chromatography (eluting with hexane/ethylacetate =3:1). The first eluted compound was the6-chloro-7-trifluoromethyl isomer, (590mg, 61%) obtained as an off-whitesolid.

hu 1H NMR (300 MHz, CDCl₃) δ=4.08 (3H,s), 7.88 (1H,br s), 8.08 (1H,s),18.43 (1H,br.,s).

The second eluted compound was the 7-chloro-6-trifluoromethyl isomer(205 mg, 21%), obtained as an off-white solid.

¹ H NMR (300 MHz, CDCl₃) δ=4.12 (3H,s), 5.65 (2H,br.,s) 7.80 (1 H,s).

(g) 3,5-Diamino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin

Hydrazine hydrate (0.34 ml, 7.0 mmol) was added to a stirred solution of3-amino-6-chloro-7-trifluoromethyl-2-methoxy-5-nitroquinoxaline (0.55g,1.7 mmol) in ethanol (25 ml) containing suspended 10%ruthenium-on-carbon (55 mg) under nitrogen at reflux. After 20 minutes,additional hydrazine hydrate (0.17 ml, 3.4 mmol) was added, and themixture was stirred at reflux for 30 minutes, then allowed to stand atroom temperature overnight. The mixture was filtered through Arbocelfilter aid, and the filter cake was washed with ethanol anddichloromethane. The filtrate was concentrated under reduced pressure togive the title compound (0.50 g, 100%) as an off-white solid.

¹ H NMR (300 MHz, CDCl₃) δ=4.13 (3H,s), 5.08 (2H,br s), 5.30 (2H,br s),7.47 (1H,s).

(h)N-(3-Amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide

Methanesulphonic anhydride (2.9 g, 16.6 mmol) was added to a stirredsolution of 3,5-diamino-6-chloro-2-methoxy-7-trifluoromethylquinoxaline(0.48 g, 1.64 mmol) and pyridine (1.34 ml, 16.6 mmol) in anhydroustetrahydrofuran under nitrogen at room temperature. After 18 h, themixture was concentrated under reduced pressure, diluted with water, andthe products extracted into ethyl acetate (three portions). The combinedorganic solutions were washed with 2M hydrochloric acid, saturatedaqueous sodium bicarbonate and saturated aqueous sodium chloride, dried(MgSO₄) and concentrated under reduced pressure to give a yellow solid(0.9 g). This material was suspended in a 25% solution of ethylamine inethanol (20 ml) at 50° C. for 2 h. The mixture was concentrated underreduced pressure, and partitioned between ethyl acetate and 2Mhydrochloric acid. The extracts were dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by flash chromatography(eluting with dichloromethane, then dichloromethane/ methanol =99:1 andfinally dichloromethane/ methanol =98:2). Fractions containing theproduct were concentrated under reduced pressure, dissolved in ethylacetate and extracted with 2M hydrochloric acid. The acid solution wasrendered basic (pH8) by the addition of saturated aqueous sodiumbicarbonate, and the product was extracted into ethyl acetate. Theorganic solution was dried (MgSO₄) and concentrated to give the titlecompound (0.25 g, 41%), as a white solid.

¹ H NMR (300 MHz, DMSO-d₆) δ=3.29 (3H,s), 4.07 (3H,s), 7.70 (2H,br s),7.90 (1H,s), 9.35 (1H,s).

m/z (thermospray) 371 (MH⁺).

PREPARATION 21N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(methoxycarbonylmethyl)-methanesulphonamide##STR84##

Anhydrous potassium carbonate (1.60 g, 11.2 mmol) was added to asuspension ofN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-methanesulphonamide (seePreparation 3, 3.0 g, 9.4 mmol) in acetone (70 ml) with stirring. Themixture was heated at reflux for 15 minutes, cooled, and methylbromoacetate (1.8 ml, 18.7 mmol) was added. The mixture was then heatedat reflux for 2 h, cooled, diluted with ethyl acetate (300 ml) andwashed with water (2×100 ml). The organic phase was dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography (gradient elution with hexane/ethyl acetate) to give thetitle compound as a white solid (3.177 g, 80%).

¹ H NMR (300 MHz, CDCl₃) δ=3.44 (3H,s), 3.71 (3H,s), 4.14 (3H,s), 4.20(3H,s), 4.37 (1H,d,J 18 Hz), 4.71 (1H,d,J 18 Hz), 7.95 (1H,s) m/z(thermospray) 424 (MH⁺).

PREPARATION 22N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-F(6-methoxypyridin-2-yl)methyl-methanesulphonamide ##STR85##

This compound was prepared by the method of Preparation 21, above, using2-(bromomethyl)-6-methoxypyridine (see Synth Commun, 24, 1367 (1994)! inplace of methyl bromoacetate. The compound was obtained as a white solid(299 mg, 84%).

¹ H NMR (300 MHz, CDCl₃) δ=3.38 (3H,s), 3.68 (3H,s), 4.07 (3H,s), 4.15(3H,s), 4.85 (1H,d,J 14 Hz), 4.99 (1H,d,J 14 Hz), 6.58 (1H,d,J 8 Hz),6.73 (1H,d,J 7 Hz), 7.40 (1H,dd,J 8 and 7 Hz), 7.92 (1H,s). m/z(thermospray) 473 (MH⁺).

PREPARATION 23 N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(1-methoxycarbonylethyl)-methanesulphonamide ##STR86##

The compound was prepared by the method of Preparation 21, above, usingmethyl 2-bromopropanoate in place of methyl bromoacetate. The productwas obtained as a mixture of two diastereomers, which were separable byflash chromatography (gradient elution with hexane/ethyl acetate). Thefirst isomer was obtained as a white solid, (1.456 g, 57%) (Rf. 0.63,hexane/ethyl acetate =1:1).

¹ H NMR (300 MHz, CDCl₃) δ=1.11 (3H,d,J 7 Hz), 3.36 (3H,s), 3.82 (3H,s),4.15 (3H,s), 4.18 (3H,s), 5.10 (1H,q,J 7 Hz), 7.96 (1H,s).

m/z (thermospray) 438 (MH⁺).

The second isomer was also obtained as a white solid (0.75 g, 29%) (Rf0.45, hexane/ethyl acetate =1:1).

¹ H NMR (300 MHz, CDCl₃) δ=1.26 (3H,d,J 7 Hz), 3.36 (3H,s), 3.61 (3H,s),4.15 (3H,s), 4.21 (3H,s), 4.98 (1H,q,J 7 Hz), 7.97 (1H,s).

m/z (thermospray) 438 (MH⁺).

PREPARATION 24 5-Amino-7-chloro-6-fluoro-2,3-dimethoxyquinoxaline and5-amino-6-chloro-7-fluoro-2, 3-dimethoxyquinoxaline ##STR87##

(a) 1,4-Dihydro-6-chloro-7-fluoroquinoxalin-2,3-dione (see Example 17,WO94/00124) (0.200 g, 0.93 mmol) was added in portions to fuming nitricacid (density, 1.5 g.cm⁻³, 5 ml) at room temperature. After 30 minutes,the mixture was added to water (50 ml). The resulting solid was filteredoff and dried in vacuo to give a 6:1 mixture of1,4-dihydro-6-chloro-7-fluoro-5-nitroquinoxalin-2, 3-dione and1,4-dihydro-7-chloro-6-fluoro-5-nitroquinoxalin-2, 3-dione (0.095 g,39%) as a pale orange solid.

¹ H NMR (300 MHz, DMSO-d₆) δ=7.24 (1H major, d,J 10 Hz), 7.39 (1H minor,d,J 8Hz), 12.17 (1H major, 1H minor. br s), 12.29 (1H major, 1H minor,br s).

m/z (thermospray) 277, 279 (MNH₄ ⁺).

(b) The mixture of intermediates from (a) above was converted by themethod of Preparation 1(a) into a 6:1 mixture of2,3,6-trichloro-7-fluoro-5-nitroquinoxaline and2,3,7-trichloro-6-fluoro-5-nitroquinoxaline. The mixture of products wasobtained as a pale yellow solid (92% yield).

¹ H NMR (300 MHz, CDCl₃) δ=7.90 (1H major, d,J 10 Hz), 8.28 (1H minor,d,J 8 Hz).

(c) The mixture of intermediates from (b) above was converted into a 6:1mixture of 5-amino-2,3,6-trichloro-7-fluoroquinoxaline and 5-amino-2,3,7-trichloro-6-fluoroquinoxaline by the method of Preparation 1(b). Themixture of products was obtained as a yellow solid (100% yield).

¹ H NMR (300 MHz, CDCl₃) δ=4.92 (2H minor, br s), 5.45 (2H major, br s),7.08 (1H major, d,J 10 Hz), 7.38 (1H minor d, J 8 Hz). m/z (thermospray)267 (MH⁺).

(d) The mixture of intermediates from (c) above was converted into amixture of 5-amino-6-chloro-7-fluoro-2,3-dimethoxyquinoxaline and5-amino-7-chloro-6-fluoro-2,3-dimethoxyquinoxaline by the method of

Preparation 1(c). The mixture of products was separated by flashchromatography (elution with toluene) to afford5-amino-6-chloro-7-fluoro-2, 3-dimethoxyquinoxaline as a white solid(27% yield), m.p. 199°-200° C.

¹ H NMR (300 MHz, CDCl₃) δ=4.15 (6H,s), 5.04 (2H,br s), 6.90 (1H,d,J 10Hz).

m/z (thermospray) 258,260 (MH⁺).

5-Amino-7-chloro-6fluoro-2,3-dimethoxyquinoxaline was obtained as awhite solid (6% yield), m.p. 198°-199° C.

¹ H NMR (300 MHz, CDCl₃) δ=4.14 (3H,s), 4.18 (3H,s), 4.62 (2H,br s),7.40 (1H,d,J 8 Hz).

m/z (thermospray): 258,260 (MH⁺)

PREPARATION 25N-(7-Chloro-6fluoro-2,3-dimethoxyquinoxalin-5-yl-methanesulphonamide##STR88##

Methanesulphonic anhydride (0.55 g, 3.16 mmol) and pyridine (255 μl,3.15 mmol) were added to a stirred suspension of5-amino-7-chloro-6-fluoro-2,3-dimethoxyquinoxaline (see Preparation 24)(0.274 g, 1.06 mmol) in dichloromethane (15 ml) at room temperatureunder nitrogen. The mixture was stirred at room temperature overnight,concentrated to dryness and suspended in tetrahydrofuran (30 ml). Thereaction mixture was treated with 1M sodium hydroxide (5.3 ml, 5.3 mmol)with ice-cooling, followed by stirring at 5° C. for 1.5 h. The reactionmixture was acidified to pH2 with 2M hydrochloric acid, concentrated andpartitioned between water and dichloromethane. The layers were separatedand the aqueous layer was extracted with dichloromethane twice. Thecombined organics were dried (MgSO₄) and concentrated to give a paleyellow solid. Suspension in THF (30 ml) and treatment with 1M sodiumhydroxide (5.3 ml, 5.3 mmol) at 5° C. was followed by stirring at roomtemperature for 2 h. The reaction mixture was acidified to pH2 with 2Mhydrochloric acid, concentrated to a small volume, diluted with waterand filtered. The filtrate was washed with water and cold diethyl etherto afford a white solid (0.32 g, 90%), m.p. 227°-228° C.

¹ H NMR (300 MHz, DMSO-d₆) δ=3.12 (3H,s), 4.04 (3H,s), 4.12 (3H,s), 7.90(1H,d,J 8 Hz), 9.50 (1H,s). m/z (thermospray) 336, 338 (MH⁺).

PREPARATION 26N-(6-Chloro-7-fluoro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide##STR89##

5-Amino-6-chloro-7-fluoro-2,3-dimethoxyquinoxaline (see Preparation 24)was converted by the method of Preparation 25 intoN-(6-Chloro-7-fluoro-2, 3-dimethoxyquinoxalin-5-yl)methanesulphonamide.The product was obtained as a white solid (30% yield).

¹ H NMR (300 MHz, DMSO-d₆) δ=3.16 (3H,s), 4.04 (3H,s), 4.12 (3H,s), 7.72(1H,d,J 10 Hz), 9.60 (1H,s).

m/z (thermospray) 336, 338 (MH⁺).

PREPARATION 27N-(6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide ##STR90##

(a) N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added to arefluxing mixture ofN-(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yI)-methanesulphonamide(Preparation 3, 2.00 g, 5.68 mmol) and potassium carbonate (1.88 g,13.63 mmol) in acetone (100 ml) under nitrogen. After 48 hours, furtherN-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added and refluxingcontinued for 18 hours. After cooling the mixture was concentrated underreduced pressure and the residue dissolved in dichloromethane. Theresulting solution was washed twice with 1N sodium hydroxide solution,water and brine and then dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by flash chromatography (eluting withhexane:ethyl acetate) to affordN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide as a pale yellow solid (2.55g, 85%).

¹ H NMR (300 MHz, CDCl₃) δ=3.25 (3H,s), 3.64 (2H,t,J 8 Hz), 3.90-4.02(2H,m), 4.12 (3H,s), 4.17 (3H,s), 7.65-7.80 (3H,m), 7.82-7.92 (2H,m).m/z (thermospray) 525 (MH⁺).

(b) A 33% solution of methylamine in IMS (industrial methylated spirits)(1.77 ml, 19.03 mmol) was added to a stirred solution ofN-(6,7-dichloro-2, 3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide (2.00 g, 3.81 mmol) in dichloromethane (38 ml) in anitrogen filled flask equipped with a rubber septum. The mixture wasstirred for 72 hours and then further 33% methylamine in IMS solution(1.77 ml, 19.03 mmol) was added. The mixture was stirred for 18 h andthen concentrated under reduced pressure. The residue was dissolved indichloromethane and extracted twice with 10% aqueous citric acid. Theorganic layer was concentrated under reduced pressure to affordN-(6,7-dichloro-2, 3-dimethoxyquinoxalin-5-yl)-N-(N'-(2-methylaminocarbonyl!benzoyl) aminoethyl)methanesulphonamide as a solid(996 mg, 49%).

¹ H NMR (300 MHz, CDCl₃) δ=2.92 (3H,d,J5 Hz), 3.20 (3H,s), 3.45-3.62(2H,m), 3.97 (3H,s), 3.98-4.10 (2H,m), 4.13 (3H,s), 6.60 (1H,br d), 7.44(1H,m), 7.60 (1H,m), 7.72 (1H,m), 7.83 (1H,m), 7.95 (1H,s).

m/z (thermospray) 556 (MH⁺).

(c) Hydrazine hydrate (26 μl, 26 mg, 0.531 mmol) was added dropwise to asolution of N-(6,7-dichloro-2,3-dimethyoxyquinoxalin-5-yl)-N-(N'-(2-methylaminocarbonyl!benzoyl)aminoethyl)methanesulphonamide (283 mg,0.531 mmol) in dichloromethane (5 ml) and the mixture was refluxed for 4h. Methanol (1 ml) was added and refluxing continued for 18 h. Aftercooling the mixture was concentrated under reduced pressure. The residuewas dissolved in ethyl acetate and extracted with 10% citric acid. Theaqueous layer was adjusted to pH8 with solid potassium carbonate andextracted twice with dichloromethane. The combined organic layers weredried (MgSO₄) and concentrated under reduced pressure to giveN-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)methanesulphonamide as a pale yellow solid (138 mg, 66%).

¹ H NMR (300 MHz, CDCl₃) δ=2.70-2.88 (2H,m), 3.11 (3H,s), 3.79 (2H,t,J 8Hz), 4.17 (3H,s), 4.20 (3H,s), 7.95 (1H,s). m/z (thermospray) 395 (MH⁺).

PREPARATION 28 5-Bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline##STR91##

(a) A solution of 2,4,5-trichloronitrobenzene (Jpn. Kokai Tokyo Koho JP81,169,651 (1980), Chem. Abstr. 1981,96, 162307 q)(103 g, 0.46 mol) andt-butyl chloroacetate (79 ml, 0.55 mol) in dry tetrahydrofuran (400 ml)was added dropwise over 30 minutes to a solution of potassium t-butoxide(128 g, 1.14 mol) in dry tetrahydrofuran (800 ml) with stirring, undernitrogen keeping the temperature at -40° C. After the addition wascomplete, the resulting dark blue solution was stirred for a further 30minutes. The mixture was poured into 0.5M hydrochloric acid (2 L) andthe product was extracted into ethyl acetate (2.5L and 1 L). Thecombined organic solutions were dried (MgSO₄) and evaporated onto silicagel (70-200 m, 200 g). The silica gel was applied to the top of a silicagel chromatography column (800 g), and the product was eluted using ahexane/ethyl acetate gradient. Product-containing fractions werecombined and evaporated to give a yellow solid, which was trituratedwith hexane to give t-butyl 2-nitro-3,5,6-trichlorophenylacetate (91.8g, 59%) as a white solid.

Found C, 42.32; H, 3.50; N, 4.03 C₁₂ H₁₂ Cl₃ NO₄ requires C,42.32; H,3.55; N, 4.11%.

¹ H NMR (300 MHz, CDCl₃) δ=1.42 (9H,s), 3.73 (2H,s), 7.60 (1H,s) m/z(thermospray) 357 (MNH₄ ⁺).

(b) A mixture of t-butyl 2-nitro-3,5,6-trichlorophenylacetate (from step(a), 123 g, 0.361 mol), and saturated aqueous ammonia (300ml) in2-methoxy ethanol (360 ml) was heated in an autoclave at 150° C. for 72h. The resulting viscous, black mixture was diluted with water (1 L) andethyl acetate (1 L) and filtered through Arbocel filter aid. The darkred filtrate was separated, and the aqueous layer extracted with ethylacetate (2×1 L). The combined organic solutions were washed with brine(1 L), dried (MgSO₄) and evaporated onto silica gel (70-200 m, 200 g).The silica gel was applied to the top of the chromatography columncontaining silica gel (40-60 m, 800 g). Elution with hexane/ethylacetate (98:2-92:8) gave 3-amino-5,6-dichloro-2-nitrotoluene (Eur. Pat.385,850) as a bright orange solid (39.7 g), which was contaminated with5-amino-3,6-dichloro-2-nitrotoluene (14%). This mixture was carried ontothe next step without further purification.

¹ H NMR (300 MHz, CDCl₃) δ=2.48 (3H,s), 4.80 (2H,s), 6.82 (1H,s).

(c) A solution of sodium dithionite (94 g, 0.54 mol) in water (1 L) wasadded to a stirred mixture of 3-amino-5,6-dichloro-2-nitrotoluene (fromstep (b), 39.7 g, 0.18 mol) and potassium bicarbonate (94 g, 0.94 mmol)in methanol (1 L) at room temperature. After 30 minutes, the mixture wasconcentrated under reduced pressure and the resulting suspensionextracted with ethyl acetate (total of 700mi). The extracts were dried(MgSO₄) and concentrated under reduced pressure to give2,3-diamino-5,6-dichlorotoluene (26.1 g, 38% over 2 steps) as a brownsolid.

¹ H NMR (300 MHz, CDCl₃) δ=2.28 (3H,s), 3.36 (2H,br s), 3.42 (2H,br s),6.72 (1H,s).

(d) A mixture of 2,3-diamino-5,6-dichlorotoluene (from step (c), 21.6 g,0.137 mol) and oxalic acid (18.45 g, 0.206 mol) in hydrochloric acid(4M, 900 ml) was heated at reflux for 6 hours, cooled and filtered. Thedark brown solid was suspended in diethyl ether, filtered and washedwith more ether to give 6,7-dichloro-5-methyl-quinoxalin-2,3-dione(22.06 g, 66%).

¹ H NMR (300 MHz, DMSO) δ=2.40 (3H,s), 7.14 (1H,s), 11.37 (1H,s), 11.94(1H,s).

(e) A mixture of 6,7-dichloro-5-methylquinoxalin-2,3-dione (from step(d) 22.06 g, 90 mmol), thionyl chloride (300 ml) and dimethylformamide(1 ml) was heated at reflux for 3 hours, cooled and poured slowly intoiced water. The resulting dark yellow precipitate was filtered off togive 5-methyl-2,3, 6,7-tetrachloroquinoxaline (24.42 g, 96%).

¹ H NMR (300 MHz, CDCl₃) δ=2.85 (3H,s), 8.02 (1 H,s).

(f) A solution of sodium methoxide (38 ml, 25% solution in methanol, 175mmol) was added over 10 minutes to a solution of5-methyl-2,3,6,7-tetrachloroquinoxaline (from step (e), 21 g, 74 mmol)in dry tetrahydrofuran (200 ml) at 20° C. There was a mildly exothermicreaction followed by formation of a precipitate. After 1 h the mixturewas diluted with ethyl acetate (3 L), washed with water (1 L), dried(MgSO₄) and concentrated under reduced pressure to give6,7-dichloro-2,3-dimethoxy-5-methylquinoxaline (20.3 g, 100%).

¹ H NMR (300 MHz, CDCl₃) δ=2.75 (3H,s), 4.15 (3H,s), 4.18 (3H,s), 7.78(1H,s).

m/z (thermospray) 273 (MH⁺).

(g) A mixture of 6,7-dichloro-2,3-dimethoxy-5-methylquinoxaline (fromstep (f), 22.0 g, 80.5 mmol), N-bromosuccinimide (17.2 g, 96.6 mmol) andα,α-azoisobutyronitrile (1.3 g, 8.0 mmol) was heated at reflux in1,1,1-trichloroethane (400 ml) for 4 h under irradiation from a 500 Wsunlamp. The mixture was cooled, silica gel (50 g, 60-230 m) was added,and the solvent was removed under reduced pressure. The residue wasapplied to the top of a silica gel chromatography column, and theproduct was eluted using a hexane/ethyl acetate gradient. The productwas triturated with hexane to give5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (25.3 g, 87%) as afluffy white solid. Found: C, 37.72; H, 2.40; N, 7.40; C₁₁ H₉ BrCl₂ N₂O₂ requires C,37.53; H, 2.58; N, 7.96%.

¹ H NMR (300 MHz, CDCl₃) δ=4.15 (3H,s), 4.22 (3H,s), 5.20 (2H,s), 7.89(1H,s).

PREPARATION 29 (6,7-Dichloro-2,3-dimethoxyquinoxalin-5-yl)methyl methylsulphone ##STR92##

(a) Sodium methanethiolate (22 mg, 0.312 mmol) was added to a stirredsolution of 5-bromomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (seePreparation 28) (100 mg, 0.284 mmol) in dry dimethylformamide (5 ml)under nitrogen at room temperature. The mixture was stirred for 10minutes and was then quenched with brine and extracted twice withdichloromethane. The combined extracts were dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified by flashchromatography (eluting with 1:1 hexane:dichloromethane) to give6,7-dichloro-2, 3-dimethoxy-5-methylthiomethylquinoxaline (79 mg, 87%)as a white solid, m.p. 143°-5° C.

¹ H NMR (300 MHz, CDCl₃) δ=2.10 (3H,s), 4.12 (3H,s), 4.15 (3H,s), 4.39(2H,s), 7.81 (1H,s).

m/z (thermospray) 319 (MH⁺).

(b) 3-Chloroperoxybenzoic acid (50%, 1.904 g, 5.52 mmol) was added inportions to a stirred solution of6,7-dichloro-2,3-dimethoxy-5-methylthiomethylquinoxaline (step (a),800mg, 2.51 mmol) in dry dichloromethane (30 ml) at room temperatureunder nitrogen. The mixture was stirred for 30 minutes and was thenquenched with 10% aqueous sodium sulphite solution and the organic layerseparated. The dichloromethane solution was washed with 10% aqueouspotassium carbonate solution, dried (MgSO₄) and concentrated underreduced pressure to leave(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yl)methyl methyl sulphone(980mg, >100% contains some dichloromethane) as a white solid, m.p.161°-3° C.

¹ H NMR (300 MHz, CDCl₃) δ=2.92 (3H,s), 4.13 (3H,s), 4.19 (3H,s), 5.16(2H,s), 7.94 (1H,s).

m/z (thermospray) 351 (MH⁺).

PREPARATION 30 (6.7-Dichloro-2.3-dimethoxyquinoxalin-5-yl)methyl ethylsulphone ##STR93##

The title compound was prepared from the compound of Preparation 28 bythe method of Preparation 29 (a) and (b) using sodium ethanethiolate,and was obtained as an off-white solid (31% for two steps), m.p. 150°-2°C.

¹ H NMR (300 MHz, CDCl₃) δ=1.43 (3H,t,J 8 Hz), 3.08 (2H,q,J 8Hz), 4.16(3H,s), 4.21 (3H,s), 5.14 (2H,s), 7.96 (1H,s).

m/z (thermospray) 365 (MH⁺).

PREPARATION 31 (6.7-Dichloro-2.3-dimethoxyquinoxalin-5-yl)methyl benzylsulphone ##STR94##

(a) Potassium carbonate (108 mg, 0.781 mmol) followed by benzylmercaptan (92 μl, 97 mg, 0.781 mmol) were added to a stirred solution of5-bromomethyl-6,7-dichloro-2,3-methoxyquinoxaline (Preparation 28) (250mg, 0.71 mmol) in dry dimethylformamide (10 ml) under nitrogen at roomtemperature. The mixture was stirred for 30 minutes and was thenpartitioned between brine and ethyl acetate. The organic layer wasseparated and the aqueous phase was extracted twice with ethyl acetate.The combined extracts were dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by flash chromatography (eluting with3:1 then 2:1 hexane:dichloromethane) to give5-benzylthiomethyl-6,7-dichloro-2,3-dimethoxyquinoxaline (268 mg, 96%)as a white solid, m.p. 121°-122° C.).

¹ H NMR (300 MHz, CDCl₃) δ=3.86 (2H,s), 4.00 (3H,s), 4.14 (3H,s), 4.43(2H,s), 7.25 (5H,m), 7.80 (1H,s).

m/z (thermospray) 395 (MH⁺).

(b) The title compound was prepared from5-benzylthiomethyl-6,7-dichloro-2, 3-dimethoxyquinoxaline (step (a)) bythe method of Preparation 29 (b) and was obtained as a white solid(93%), m.p. 185°-7° C.

¹ H NMR (300 MHz, CDCl₃) δ=4.03 (3H,s), 4.12 (3H,s), 4.35 (2H,s), 5.12(2H,s), 7.40 (5H,m), 7.93 (1H,s). m/z (thermospray) 427 (MH⁺).

We claim:
 1. A compound of formula I, ##STR95## wherein A represents Nor CH;R¹ and R² independently represent C₁₋₄ alkyl, halo or CF₃ ; R³represents C₁₋₄ alkyl (optionally substituted by C₃₋₇ cycloalkyl oraryl), C₃₋₇ cycloalkyl, CF₃ or aryl; R⁴ represents H, C₃₋₇ cycloalkyl orC₁₋₆ alkyl; R⁵ and R⁶ independently represent H or C₁₋₄ alkyl, or takentogether with the nitrogen atom to which they are attached they mayrepresent a pyrrolidino, piperidino or morpholino group; and nrepresents 2, 3 or 4;or a pharmaceutically acceptable salt thereof.
 2. Acompound as claimed in claim 1, wherein A represents N.
 3. A compound asclaimed in claim 1, wherein R¹ represents halo or C₁₋₄ alkyl.
 4. Acompound as claimed in claim 1, wherein R² represents halo or C₁₋₄alkyl.
 5. A compound as claimed in claim 1, wherein R³ represents C₁₋₄alkyl.
 6. A compound as claimed in claim 5, wherein R³ representsmethyl.
 7. A compound as claimed in claim 1, wherein R⁴ represents C₁₋₆alkyl substituted by OH or CO₂ H.
 8. A compound as claimed in claim 7,wherein R⁴ represents CH₂ CH₂ OH or CH₂ CO₂ H.
 9. A compound as claimedin claim 2, wherein the chirality of the bond between the nitrogen atomrepresented by A and the 1,4-dihydro-2,3-dioxoquinoxaline ring is asshown in formula IA, ##STR96## wherein R¹⁻⁴ are as defined in claim 1.10. A compound as claimed in any claim 1, which is(R)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)-N-(2-hydroxyethyl)methane-sulphonamide.11. A compound as claimed in claim 1, which is(R)-N-(carboxymethyl)-N-(1,4-dihydro-6,7-dichloro-2,3-dioxoquinoxalin-5-yl)methane-sulphonamide.12. A pharmaceutical composition comprising a compound of the formula(I), or a pharmaceutically acceptable salt thereof, as claimed accordingto claim 1, together with a pharmaceutically acceptable carrier ordiluent.
 13. The method of treating neurodogenerative disorder in apatient in need of such treatment, which comprises administering to saidafflicted subject a therapeutically-effective amount of a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, asclaimed in claim 1.